1,3-bis-(substituted-phenyl)-2-propen-1-ones and their use to treat VCAM-1 mediated disorders

ABSTRACT

It has been discovered certain 1,3-bis-(substituted-phenyl)-2-propen-1-ones, including compounds of formula (I) inhibit the expression of VCAM-1, and thus can be used to treat a patient with a disorder mediated by VCAM-1. Examples of inflammatory disorders that are mediated by VCAM-1 include, but are not limited to arthritis, asthma, dermatitis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosis, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, rhinitis, ischemia-reperfusion injury, post-angioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina and small artery disease.

This application is a continuation U.S. Ser. No. 09/886,348, filed Jun.20, 2001, which claims priority to U.S. Ser. No. 60/212,769, filed onJun. 20, 2000, and U.S. Ser. No. 60/255,934 filed on Dec. 15, 2000, thedisclosures of which are hereby incorporated by reference in theirentirety.

The present invention includes novel heteroaryl or heterocyclic1,3-bis-(substituted-phenyl)-2-propen-1-ones as well as methods andcompositions for the treatment of disorders mediated by VCAM-1 or MCP-1and for the treatment of inflammatory disorders generally that includethe administration of a 1,3-bis-(substituted-phenyl)-2-propen-1-one thathas at least one phenyl substituent that is an aryl, heteroaryl orheterocyclic moiety.

BACKGROUND OF THE INVENTION

Adhesion of leukocytes to the endothelium represents a fundamental,early event in a wide variety of inflammatory conditions, autoimmunedisorders and bacterial and viral infections. Leukocyte recruitment toendothelium is mediated in part by the inducible expression of adhesionmolecules on the surface of endothelial cells that interact withcounterreceptors on immune cells. Endothelial cells determine whichtypes of leukocytes are recruited by selectively expressing specificadhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1),intercellular adhesion molecule-1 (ICAM-1), and E-selectin. VCAM-1 bindsto the integrin VLA-4 expressed on lymphocytes, monocytes, macrophages,eosinophils, and basophils but not neutrophils. This interactionfacilitates the firm adhesion of these leukocytes to the endothelium.VCAM-1 is an inducible gene that is not expressed, or expressed at verylow levels, in normal tissues. VCAM-1 is upregulated in a number ofinflammatory diseases, including arthritis, asthma, dermatitis,psoriasis, cystic fibrosis, post transplantation late and chronic solidorgan rejection, multiple sclerosis, systemic lupus erythematosis,inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy,rhinitis, ischemia-reperfusion injury, post-angioplasty restenosis,chronic obstructive pulmonary disease (COPD), glomerulonephritis, Gravesdisease, gastrointestinal allergies, conjunctivitis, atherosclerosis,coronary artery disease, angina and small artery disease.

Coronary heart disease (CHD), primarily as a result of atherosclerosis,remains the leading cause of death in industrialized countries.Atherosclerosis is a disease characterized by vascular inflammation,deposition of lipids in the arterial vessel wall and smooth muscle cellproliferation resulting in a narrowing of the vessel passages. Inadvanced stages of the disease atherosclerotic lesions can becomeunstable resulting in plaque rupture, thrombosis, myocardial infarctionand ischemic heart disease. It is now well accepted that the initiatingevents in atherosclerosis are local injury to the arterial endotheliumthat results in the induction of VCAM-1 and recruitment of mononuclearleukocytes that express the integrin counterreceptor, VLA-4, (O'Brien,et al., J. Clin. Invest., 92: 945-951, 1993). Subsequent conversion ofleukocytes to foamy macrophages results in the synthesis of a widevariety of inflammatory cytokines, growth factors, and chemoattractantsthat help propagate formation of the mature atheromatous plaque byfurther inducing endothelial activation, leukocyte recruitment, smoothmuscle cell proliferation, and extracellular matrix deposition.Pharmacological inhibition of VCAM-1 expression has been shown toinhibit atherosclerosis in several animal models (Sundell et al.,Circulation, 100: 42, 1999). A monoclonal antibody against VCAM-1 hasalso been shown to inhibit neointimal formation in a mouse model ofarterial wall injury (Oguchi, S., et al., Arterioscler. Thromb. Vasc.Biol., 20: 1729-1736, 2000).

Asthma, which is increasing in prevalence and morbidity world-wide, is achronic inflammatory disease characterized by lung eosinophilia andbronchial hyperreactivity. The interaction between VCAM-1 on lungendothelial cells and VLA-4, which is the integrin counterreceptorexpressed on eosinophils, is thought to be important for selectiveeosinophil recruitment. Eosinophils have been considered an importanteffector cell in the pathogenesis of asthma and other allergic diseases.Activated eosinophils release proteins such as major basic protein (MBP)that have been demonstrated to induce bronchial hyperreactivity, one ofthe defining criteria of asthma (Bousquot, et al., N. Engl. J. Med.,323: 1033-1039, 1990). It has been demonstrated that VCAM-1 is markedlyupregulated on human bronchial vascular endothelium of subjects withasthma who have air flow limitation, when compared with subjects withoutasthma (Pilewski, et al., Am. J. Respir. Cell Mol. Biol., 12, 1-3,1995;Ohkawara, Y., et al., Am. J. Respir. Cell Mol. Biol., 12, 4-12, 1995;Gosset, P., et al., Int. Arch. Allergy Immunol. 106: 69-77, 1995;Hacken, N. H., et al., Clin. Exp. Allergy, 28 (12): 1518-1525, 1998). Anelevation in serum soluble VCAM-1 levels has also been demonstrated inpatients undergoing a bronchial asthma attack compared with levels understable conditions (Montefort, S., Koizumi, A., Clin. Exp. Immunol., 101:468-73, 1995). Several animal studies further demonstrate a spatial andtemporal association between VCAM-1 and asthma. In a mouse model ofallergic asthma, VCAM-1 expression was shown to be induced by allergenchallenge, and administration of an anti-VCAM-1 antibody was effectivein inhibiting eosinophil infiltration that occurred in this model(Metzger, W. J., et al., J. Allergy Clin. Immunol., 93: 183, 1994).Further evidence for the importance of VCAM-1 in allergic asthma comesfrom work in IL-12 knockout mice. IL-12 knockout mice had fewereosinophils and VCAM-1 expression than wildtype mice; however,administration of recombinant IL-12 at the time of ova sensitization andchallenge restored lung VCAM-1 expression and eosinophilia (Wang, S., etal., J. Immunol., 166:2741-2749, 2001). There are several examples whereblocking the integrin receptors for VCAM-1 have had positive effects onanimal models of asthma (Rabb et al., Am. J. Respir. Care Med. 149:1186-1191, 1994; Abraham, W, et al., Am. J. Respir. Crit. Care Med. 156:696-703. 1997) further demonstrating the importance of VCAM-1/VLA-4interactions in allergic inflammation. Eosinophils are also importanteffector cells in allergic rhinitis. VCAM-1 has been demonstrated to beupregulated 24 hrs after nasal allergen provocation in patients withseasonal allergic rhinitis but not in normal subjects (Braunstahl, G.J., et al., J. Allergy Clin. Immunol., 107: 469-476, 2001).

Rheumatoid arthritis (RA) is a clinical syndrome of unknown causecharacterized by symmetric, polyarticular inflammation of synovial-linedjoints. The role of adhesion molecules in the pathogenesis of rheumatoidarthritis (RA) has also been well documented, and VCAM-1 expression onsynovial fibroblasts is a clinical hallmark of RA (Li, P., et al., J.Immunol. 164: 5990-7, 2000). VLA-4/VCAM-1 interactions may be thepredominant mechanism for recruitment of leukocytes to the synovium(Dinther-Janssen, et al., J. Immunol. 147: 4207-4210, 1991; Issekeutzand Issekeutz, Clin. Immunol. Immunopathol. 61:436-447, 1991;Morales-Ducret et al., J. Immunol. 149:1424-1431, 1992; Postigo et al.,J. Clin. Invest. 89:1445-1452, 1992; Matsuyama, T., et al, Hum. Cell, 9:187-192,1996). In support of this, increased VCAM-1 expression has beenfound in RA synovial tissue compared with osteoarthritis and controltissue (Wilkinson et al., Lab. Invest. 69:82-88, 1993;Furuzawa-Carballeda, J., et al., Scand. J. Immunol. 50: 215-222; 1999).Soluble VCAM-1 is higher in RA patients than in control subjects(Kolopp-Sarda, M. N., et al., Clin. Exp. Rheumatol. 19: 165-70, 2001).Soluble VCAM-1 has been shown to be chemotactic for T cells (Kitani, A.,et al., J. Immun. 161: 4931-8, 1998), and in addition to being apossible diagnostic marker for RA, may contribute to its pathogenesis byinducing migration and recruitment of T cells. VCAM-1 expressed onfibroblast-like synoviocytes has also been implicated in enhancedsurvival of activated synovial fluid B cells (Marinova, Mutafcheia, L.,Arthritis Rheum. 43: 638-644, 2000) that may further contribute to RApathogenesis.

Chronic inflammation and accompanying vascular complications and organdamage characterize systemic lupus erythematosis (SLE). Recent studiessuggest that VCAM-1 plays a role in SLE. Expression of VCAM-1 isincreased on dermal vessel endothelial cells in patients with activesystematic lupus erythematosus (Jones, S. M., British J. Dermatol. 135:678-686, 1996) and correlates with increased disease severity (Belmontet al., Arthritis Rheum. 37:376-383, 1994). SLE muscle samples withperivascular infiltrate have greater endothelial cell expression ofVCAM-1 compared with SLE patients without a perivascular infiltrate orwith control samples (Pallis et al., Ann. Rheum. Dis. 52:667-671, 1993).Increased expression of VCAM-1 has also been demonstrated in kidneys oflupus-prone MRL/1 pr mice compared to nonautoimmune strains and itsexpression increased with disease severity (McHale, J. F., et al., J.Immunol. 163: 3993-4000, 1999). VCAM-1 expression on mesangial cells invitro can be stimulated by IL-1, TNF-α, and INFγ exposure as well as byanti-endothelial cell IgG fraction and anti-DNA autoantibodies from SLEpatients (Wuthrich, Kidney Int. 42: 903-914, 1992; Papa, N. D., et al.,Lupus, 8: 423-429, 1999; Lai, K. N., et al., Clin Immunol Immunopathol,81: 229-238, 1996). Furthermore, soluble VCAM-1 is higher in SLEpatients than in normal subjects (Mrowka, C., et al., Clin. Nephrol. 43:288-296, 1995; Baraczka, K., et al., Acta. Neurol. Scand. 99: 95-99,1999; Kaplanski, G., et al., Arthritis Rheumol. 43: 55-64, 2000; Ikeda,Y., Lupus, 7: 347-354, 1998) and correlates with disease activity(Scudla, V., Vnitr. Lek., 43: 307-311, 1997).

Increased VCAM-1 expression has also been demonstrated in solid organtransplant rejection. Acute transplant rejection occurs when thetransplant recipient recognizes the grafted organ as “non-self” andmounts an immune response characterized by massive infiltration ofimmune cells, edema, and hemorrage that result in the death of thetransplanted organ. Acute rejection occurs in a matter of hours or daysand has been correlated with increased levels of VCAM-1 in tissues andin plasma (Tanio et al., Circulation, 89:1760-1768, 1994; Cosimi et al.,J. Immunol. 144: 4604-4612, 1990; Pelletier, R., et al.,Transplantation, 55: 315, 1992). A monoclonal antibody to VCAM-1 hasbeen shown to inhibit cardiac allograft rejection in mice (Pelletier,R., J. Immunol., 149: 2473-2481, 1992; Pelletier, R., et al.,Transplantation Proceedings, 25: 839-841, 1993; Orosz, C. G., et al., J.Heart and Lung Transplantation, 16: 889-904, 1997) and when given for 20days can cause complete inhibition of rejection and long-term graftacceptance (Orosz C. G., et al., Transplantation, 56: 453-460, 1993).Chronic graft rejection also known as allograft vasculopathy is distinctfrom acute transplant rejection and is a leading cause of late graftloss after renal and heart transplantation. Histologically it ischaracterized by concentric neointimal growth within vessels that islargely due to smooth muscle migration and proliferation. It is thoughtto be the result of endothelial damage brought about by several factorsincluding: ischemia-reperfusion injury, immune complexes, hypertension,hyperlipidemia and viruses. All of these factors have been associatedwith induction of VCAM-1 in endothelial cells. There is also a strongcorrelation of soluble and tissue VCAM-1 levels with chronic rejection(Boratynska, M.,. Pol. Arch. Med. Wewn, 100: 410-410, 1998; Zembala, M.,et al., Ann. Transplant. 2: 16-9, 1998; Solez K., et al., KidneyInternational., 51: 1476-1480, 1997; Koskinen P. K., et al.,Circulation, 95: 191-6, 1997).

Multiple sclerosis is a common demyelinating disorder of the centralnervous system, causing patches of sclerosis (plaques) in the brain andspinal cord. It occurs in young adults and has protean clinicalmanifestations. It is well documented that VCAM-1 is expressed on brainmicrovascular endothelial cells in active lesions of multiple sclerosis(Lee S. J., et al., J. Neuroimmunol., 98: 77-88, 1998). Experimentaltherapy of experimental autoimmune encephalomyelitis, which is an animalmodel for multiple sclerosis, using antibodies against several adhesionmolecules, including VCAM-1, clearly shows that adhesion molecules arecritical for the pathogenesis of the disease (Benveniste et al., J.Neuroimmunol. 98:77-88, 1999). A time and dose dependent expression ofVCAM-1 and release of soluble VCAM-1 were detected in cultures of humancerebral endothelial cells induced by TNFα, but not in peripheral bloodmononuclear cells (Kallmann et al., Brain, 123:687-697, 2000). Clinicaldata also show that adhesion molecules in blood and cerebrospinal fluidare up-regulated throughout the clinical spectrum of multiple sclerosis(Baraczka, K., et al., Acta. Neurol. Scand. 99: 95-99, 1999; Reickimann,P., et al., Mult. Scler., 4: 178-182, 1998; Frigerio, S., et al., J.Neuroimmunol., 87: 88-93, 1998) supporting the notion that therapieswhich interfere with cell adhesion molecules such as VCAM-1 may bebeneficial in modifying this disease (Elovaara et al., Arch. Neurol.57:546-551, 2000).

Diabetes mellitus is a metabolic disease in which carbohydrateutilization is reduced and that of lipid and protein is enhanced.Evidence has accumulated that increased levels of adhesion molecules mayplay a functional pathophysiological role in diabetes (Wagner and Jilma,Hormone and Metabolic Research, 29: 627-630, 1997; Kado, S., DiabetesRes. Clin. Pract., 46: 143-8, 1999). It is caused by an absolute orrelative deficiency of insulin and is characterized by chronichyperglycemia, glycosuria, water and electrolyte loss, ketoacidosis, andcoma. Elevated circulating adhesion molecules including VCAM-1 have beendetected in patients with diabetes and in experimental models ofdiabetes in animals (Lorini et al., Hormone Research, 48: 153, 1997;Otsuki et al., Diabetologia, 40: A440, 1997; Hart et al., FASEB J.11:A340, 1997; Albertini et al., Diabetologia, 39: A240, 1996; Wagner etal., Diabetologia, 39: A205, 1996; Enghofer et al., Diabetologia, 39:A97, 1996; Koga M., Diabet. Med., 15: 661-667, 1998). In addition,complications of diabetes often include peripheral vasculopathies suchas diabetic retinopathy and diabetic nephropathy. It is believed thatadhesion of leukocytes to the peripheral vasculature plays a centralrole in the vasculopathies often associated with diabetes.

Crohn's disease, also known as regional enteritis, is a subacute chronicinflammatory condition of unknown cause, involving the internal ileumand less frequently other parts of the gastrointestinal tract. It ischaracterized by patchy deep ulcers that may cause fistulas, andnarrowing and thickening of the bowel by fibrosis and lymphocyticinfiltration. Ulcerative colitis is a chronic disease of unknown causecharacterized by ulceration of the colon and rectum, with rectalbleeding, mucosal crypt abscesses, inflammatory pseudopolyps, abdominalpain, and diarrhea. It has been reported that serum VCAM-1 reflects thegrade of intestinal inflammation in patients with Crohn's disease orulcerative colitis (Jones, et al., Gut, 36: 724-30, 1995; Goggins etal., Gastroenterology, 108: A825, 1995; Goeke and Manns,Gastroenterology, 106: A689, 1994; Goeke et al., J. Gasterokenterol.32:480-486, 1997; Loftus et al., Gastroenterology, 108: A684, 1995;Tahami et al., Gastroenterology, 118: A344, 2000). Antibodies to VCAM-1have been shown to ameliorate experimentally-induced colitis in mice(Soriano, A., Lab. Invest. 80: 1541-1551, 2000).

Psoriasis is a chronic skin disease characterized by erythematousscaling plaques as a result of keratinocyte hyperplasia, influx ofimmune cells and endothelial activation (Nickoloff, B. J., et al., J.Invest. Dermatol., 127: 871-884, 1991). VCAM-1 is upregulated inpsoriatic skin as compared to normal skin (Groves, R. W., J. Am. Acad.Dermatol., 29: 67-72, 1993; Uyemura, K., et al., J. Invest. Dermatol.101: 701-705, 1993) and levels of circulating VCAM-1 correlate withdisease activity (Schopf, R. E., Br. J. Dermatol., 128: 34-7, 1993).

U.S. Pat. Nos. 5,750,351; 5,807,884; 5,811,449; 5,846,959; 5,773,231,and 5,773,209 to Medford, et al., as well as the correspondingWO95/30415 to Emory University indicate that polyunsaturated fatty acids(“PUFAs”) and their hydroperoxides (“ox-PUFAs”), which are importantcomponents of oxidatively modified low density lipoprotein (LDL), inducethe expression of VCAM-1, but not intracellular adhesion molecule-1(ICAM-1) or E-selectin in human aortic endothelial cells, through amechanism that is not mediated by cytokines or other noncytokinesignals. This is a fundamental discovery of an important and previouslyunknown biological pathway in VCAM-1 mediated immune responses. Asnon-limiting examples, linoleic acid, linolenic acid, arachidonic acid,linoleyl hydroperoxide (13-HPODE) and arachidonic hydroperoxide(15-HPETE) induce cell-surface gene expression of VCAM-1 but not ICAM-1or E-selectin. Saturated fatty acids (such as stearic acid) andmonounsaturated fatty acids (such as oleic acid) do not induce theexpression of VCAM-1, ICAM-1 or E-selectin.

PCT WO 98/51662, filed by AtheroGenics, Inc. and listing as inventorsRussell M. Medford, Patricia K. Somers, Lee K. Hoong, and Charles Q.Meng, claims priority to provisional application U.S. Ser. No.60/047,020, filed on May 14, 1997. This application discloses the use ofa broad group of compounds as cardiovascular protectants that exhibit atleast one, and sometimes a composite profile, of reducing cholesterol,lowering LDL, and inhibiting the expression of VCAM-1.

U.S. Pat. No. 5,155,250 to Parker, et al. discloses that2,6-dialkyl-4-silylphenols are antiatherosclerotic agents. The samecompounds are disclosed as serum cholesterol lowering agents in PCTPublication No. WO 95/15760, published on Jun. 15, 1995. U.S. Pat. No.5,608,095 to Parker, et al. discloses that alkylated-4-silyl-phenolsinhibit the peroxidation of LDL, lower plasma cholesterol, and inhibitthe expression of VCAM-1, and thus are useful in the treatment ofatherosclerosis.

PCT WO 98/51289, which claims priority to provisional application U.S.Ser. No. 60/047,020, filed on May 14, 1997 by Emory University listingPatty Somers as sole inventor, discloses the use of a group of compoundsas cardiovascular protectants and antiinflammatory agents which exhibitat least one, and sometimes a composite profile, of reducingcholesterol, lowering LDL, and inhibiting the expression of VCAM-1 andthus can be used as antiinflammatory and cardivascular treat agents.

U.S. Pat. Nos. 5,380,747; 5,792,787; 5,783,596; 5,750,351; 5,821,260;5,807,884; 5,811,449; 5,846,959; 5,877,203; and 5,773,209 to Medford, etal., teach the use of dithiocarbamates of the general formula A—SC(S)—Bfor the treatment of cardiovascular and other inflammatory diseases.Examples include sodium pyrrolidine-N-carbodithioate, tri-sodiumN,N-di(carboxymethyl)-N-carbodithioate, and sodiumN,N-diethyl-N-carbodithioate. The patents teach that the compoundsinhibit the expression of VCAM-1.

PCT WO 98/23581 discloses the use of benzamidoaldehydes and their use ascysteine protease inhibitors.

PCT WO 97/12613 of Comicelli et al. discloses compounds for theinhibition of 15-lipogenase to treat and prevent inflammation oratherosclerosis. Compounds disclosed include benzopyranoindole,benzimidazole, catacholes, benzoxadiazines, benzo[a]phenothiazine, orrelated compounds thereof.

Japanese Patent No. 06092950 to Masahiko et al. discloses preparation ofepoxy compounds wherein electron deficient olefins such as acylstyrenederivatives, styrene derivatives, and cyclohexenone derivatives areefficiently oxidized by a hydrogen peroxide derivative in the presenceof a primary or secondary amine in an organic solvent to give saidepoxides which are useful intermediates for pharmaceutical and flavoringmaterials.

U.S. Pat. No. 5,217,999 to Levitzki et al. discloses substituted styrenecompound as a method of inhibiting cell proliferation.

Chalcone (1,3-bis-aromatic-prop-2-en-1-ones) compounds are naturalproducts related to flavonoids. PCT WO 99/00114 (PCT/DK98/00283)discloses the use of certain chalcones, 1,3-bis-aromatic-propan-1-ones(dihydrochalcones), and 1,3-bisaromatic-prop-2-yn-1-ones for thepreparation of pharmaceutical compositions for the treatment ofprophylaxis of a number of serious diseases including i) conditionsrelating to harmful effects of inflammatory cytokines, ii) conditionsinvolving infection by Helicobacter species, iii) conditions involvinginfections by viruses, iv) neoplastic disorders, and v) conditions causeby microorganisms or parasites.

PCT WO 00/47554 filed by Cor Therapeutics describes a broad class ofsubstituted unsaturated compounds for use as antithrombotic agents.

PCT 96/20936 (PCT/KR95/00183) discloses thiazolidin-4-one derivatives ofthe formula:

which act as PAF antagonists or 5-lipoxygenase inhibitors. The compoundsare used in the prevention and treatment of inflarnmatory and allergicdisorders mediated by platelet-activating factor and/or leukotrienes.

U.S. Pat. No. 4,085,135 discloses 2′-(carboxymethoxy)-chalcones withantigastric and antiduodenal ulcer activities.

U.S. Pat. No. 5,744,614 to Merkle et al. discloses a process forpreparing 3,5-diarylpyrazoles and various derivatives thereof byreacting hydrazine hydrate with 1,3-diaryipropenone in the presence ofsulfuric acid and an iodine compound.

U.S. Pat. No. 5,951,541 to Wehlage et al. discloses the use of salts ofaromatic hydroxy compounds, such as (hydroxyaryl)alkenone salts, asbrighteners in aqueous acidic electroplating baths. In addition theinvention discloses that such compounds have a lower vapor pressure thanthe known brighteners, as a single substance and in the electroplatingbaths,in order to avoid losses of substance. They also have high watersolubility properties.

Japanese Patent No. 07330814 to Shigeki et al. disclosesbenzylacetophenone compounds as photoinitiator compounds.

Japanese Patent No. 04217621 to Tomomi discloses siloxane chalconederivatives in sunscreens.

U.S. Pat. No. 4,085,135 to Kyogoku et al. discloses a process forpreparation of 2′-(carboxymethoxy)-chalcones having antigastric and antiduodenal activities with low toxicity and high absorptive ratio in thebody. This patent suggests that the high absorptive ratio in the body isdue to the 2′-carboxymethoxy group attached to the chalcone derivative.

U.S. Pat. No. 4,855,438 discloses the process for preparation ofoptically active 2-hydroxyethylazole derivatives which have fungicidaland plant growth-regulating action by reacting an α-β-unsaturated ketonewhich could include a chalcone or a chalcone derivative with anenantiomerically pure oxathiolane in the presence of a strongly basicorganometallic compound and at temperatures ranging from −80 to 120° C.

European Patent No 307762 assigned to Hofmann-La Roche disclosessubstituted phenyl chalcones.

E. Bakhite et al. in J. Chem. Tech. Biotech. 1992, 55, 157-161, havedisclosed a process for the preparation of some phenyloxazolederivatives of chalcone by condensing 5-(p-acetylphenyl)-2-phenyloxazolewith aromatic aldehydes.

Herencia, et al., in Synthesis and Anti-inflammatory Activity ofChalcone Derivatives, Bioorganic & Medicinal Chemistry Letters 8 (1998)1169-1174, discloses certain chalcone derivatives with anti-inflammatoryactivity.

Hsieh, et al., Synthesis and Antiinflammatory Effect of Chalcones, J.Pharm. Pharmacol. 2000, 52; 163-171 describes that certain chalconeshave potent antiinflammatory activity.

Zwaagstra, et al., Synthesis and Structure-Activity Relationships ofCarboxylated Chalcones: A Novel Series of CysLT1 (LT4) ReceptorAntagonists; J. Med. Chem., 1997, 40, 1075-1089 discloses that in aseries of 2-, 3-, and 4-(2-quinolinylmethoxy)- and 3- and4-[2-(2-quinolinyl)ethenyl]-substituted, 2′, 3′, 4′, or 5′ carboxylatedchalcones, certain compounds are CysLT1 receptor antagonists.

JP 63010720 to Nippon Kayaku Co., LTD discloses that chalconederivatives of the following formula (wherein R1 and R2 are hydrogen oralkyl, and m and n are 0-3) are 5-lipoxygenase inhibitors and can beused in treating allergies.

JP 06116206 to Morinaga Milk Industry Co. Ltd, Japan, discloseschalcones of the following structure as 5-lipoxygenase inhibitors,wherein R is acyl and R1-R5 are hydrogen, lower alkyl, lower alkoxy orhalo, and specifically that in which R is acyl and R1-R5 are hydrogen.

U.S. Pat. No. 6,046,212 to Kowa Co. Ltd. discloses heterocyclicring-containing chalcones of the following formula as antiallergicagents, wherein A represents a substituted or unsubstituted phenylgroup, a substituted or unsubstituted naphthyl group, or a group:

in which X represents a hydrogen or halogen atom or a hydroxyl, loweralkyl or lower alkoxyl group and B represents —CH═CH—,—N(R6)—, R6 is alower alkyl group or a lower alkoxyalkyl group, —O— or —S—; W represents—CH═CH— or —CH2O—, and R1-5 is the same or different and eachindependently represent a hydrogen or halogen atom, a hydroxyl, a loweralkyl, lower alkoxyl, carboxyl, cyano, alkyloxycarbonyl or tetrazolylgroup, a group —CONHR7 in which R7 represents a hydrogen atom or a loweralkyl group, or a group —O(CH2)n R8 in which R8 represents a carboxyl,alkyloxycarbonyl or tetrazolyl group and n is from 1 to 4, with theproviso that at least one of the groups R1-5 represents a carboxyl,cyano, alkyloxycarbonyl or tetrazolyl group, the group —CONHR7 or thegroup —O(CH2)nR8; or a salt or solvate thereof.

Reported bioactivies of chalcones have been reviewed by Dimmock, et al.,in Bioactivities of Chalcones, Current Medicinal Chemistry 1999, 6,1125-1149.

Given that VCAM-1 is a mediator of chronic inflammatory disorders, it isa goal of the present work to identify new compounds, compositions andmethods that can inhibit the expression of VCAM-1. A more general goalis to identify selective compounds and methods for suppressing theexpression of redox sensitive genes or activating redox sensitive genesthat are suppressed.

It is therefore an object of the present invention to provide newcompounds for the treatment of disorders mediated by VCAM-1.

It is also an object to provide new pharmaceutical compositions for thetreatment of diseases and disorders mediated by the expression ofVCAM-1.

It is a further object of the invention to provide compounds and methodsof treating disorders and diseases mediated by VCAM-1, includingcardiovascular and inflammatory diseases.

It is another object of the invention to provide compounds, compositionsand methods to treat arthritis.

It is yet another object of the invention to provide compounds,compositions and methods to treat asthma.

It is another object of the invention to provide compounds, methods andcompositions to inhibit the progression of atherosclerosis.

It is still another object of the invention to provide compounds,compositions, and methods to treat or prevent transplant rejection.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of lupus.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of inflammatory boweldisease.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of autoimmune diabetes.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of multiple sclerosis.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of diabetic retinopathy.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of rhinitis.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of ischemia-reperfusioninjury.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of post-angioplastyrestenosis.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of chronic obstructivepulmonary disease (COPD).

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of glomerulonephritis.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of Graves disease.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of gastrointestinalallergies.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of conjunctivitis.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of dermatitis.

It is a further object of the present invention to provide compounds,methods and compositions for the treatment of psoriasis.

SUMMARY OF THE INVENTION

It has been discovered certain1,3-bis-(substituted-phenyl)-2-propen-1-ones, including compounds offormula (I) inhibit the expression of VCAM-1, and thus can be used totreat a patient with a disorder mediated by VCAM-1. Examples ofinflammatory disorders that are mediated by VCAM-1 include, but are notlimited to arthritis, asthma, dermatitis, cystic fibrosis, posttransplantation late and chronic solid organ rejection, multiplesclerosis, systemic lupus erythematosis, inflammatory bowel diseases,autoimmune diabetes, diabetic retinopathy, rhinitis,ischemia-reperfusion injury, post-angioplasty restenosis, chronicobstructive pulmonary disease (COPD), glomerulonephritis, Gravesdisease, gastrointestinal allergies, conjunctivitis, atherosclerosis,coronary artery disease, angina and small artery disease.

The compounds disclosed herein can also be used in the treatment ofinflammatory skin diseases that are mediated by VCAM-1, as well as humanendothelial disorders that are mediated by VCAM-1, which include, butare not limited to psoriasis, dermatitis, including eczematousdermatitis, Kaposi's sarcoma, multiple sclerosis, as well asproliferative disorders of smooth muscle cells.

In yet another embodiment, the compounds disclosed herein can beselected to treat anti-inflammatory conditions that are mediated bymononuclear leucocytes.

In one embodiment, the compounds of the present invention are selectedfor the prevention or treatment of tissue or organ transplant rejection.Treatment and prevention of organ or tissue transplant rejectionincludes, but is not limited to treatment of recipients of heart, lung,combined heart-lung, liver, kidney, pancreatic, skin, spleen, smallbowel, or corneal transplants. The compounds can also be used in theprevention or treatment of graft-versus-host disease, such as sometimesoccurs following bone marrow transplantation.

In an alternative embodiment, the compounds described herein are usefulin both the primary and adjunctive medical treatment of cardiovasculardisease. The compounds are used in primary treatment of, for example,coronary disease states including atherosclerosis, post-angioplastyrestenosis, coronary artery diseases and angina. The compounds can beadministered to treat small vessel disease that is not treatable bysurgery or angioplasty, or other vessel disease in which surgery is notan option. The compounds can also be used to stabilize patients prior torevascularization therapy.

In addition to inhibiting the expression of VCAM-1, the1,3-bis-(substituted-phenyl)-2-propen-1-ones have the additionalproperties of inhibiting monocyte chemoattractant protein-1 (MCP-1) andsmooth muscle proliferation. MCP-1 is a chemoattractant protein producedby endothelial cells, smooth muscle cells as well as macrophages. MCP-1promotes integrin activation on endothelial cells thereby facilitatingadhesion of leukocytes to VCAM-1, and MCP-1 is a chemoattractant formonocytes. MCP-1 has been shown to play a role in leukocyte recruitmentin a number of chronic inflammatory diseases including atherosclerosis,rheumatoid arthritis, and asthma. Its expression is upregulated in thesediseases and as such inhibition of MCP-1 expression represents adesirable property of anti-inflammatory therapeutics. Furthermore,smooth muscle cell hyperplasia and resulting tissue remodeling anddecreased organ function is yet another characteristic of many chronicinflammatory diseases including atherosclerosis, chronic transplantrejection and asthma. Inhibition of the hyperproliferation of smoothmuscle cells is another desirable property for therapeutic compounds.

In one embodiment, the invention provides a compound of the formula (I)

or its pharmaceutically acceptable salt, wherein:

-   -   i) the wavy line indicates that the compound can be in the form        of the E or Z isomer;    -   ii) R22 and R23 are independently hydrogen or (C1-C4)alkyl;    -   iii) R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β and R6β are        independently    -   iv) hydrogen, alkyl, carbocycle, aryl, heteroaryl, heterocycle,        cycloalkyl, alkoxy, aryloxy, arylalkoxy, heteroaryloxy,        heteroarylalkoxy, alkylthio, alkylamino, aminoalkyl,        haloalkylthio, acyl, haloalkyl, aryloxy, amido, acylamino,        amino, dialkylamino, aminodialkyl, trifluoroalkoxy,        alkylsulfonyl, haloalkylsulfonyl, aminocarbonyl, alkenyl,        alkynyl, halogen, hydroxyl, thiol, cyano, nitro, sulfonic acid,        sulfonate, sulfate, sulfinic acid, sulfenic acid, sulfamide,        sulfonamide, sulfoxide, metal sulfinate, phosphate, phosphonate,        metal phosphonate, phosphinate, alditol, carbohydrate, amino        acid, OC(R1)2CO2H, SC(R1)2CO2H, NHCHR1CO2H, CO—R2, CO2R1,        polyoxyalkylene, polyol alkyl, oxyalkylamino,        alkylcarbonylalkyl, lower alkyl S(O)-lower alkyl, lower        alkyl-S(O)2-lower alkyl; hydroxyalkyl, aralkoxy, heteroaryl        lower alkoxy, heterocyclo lower alkoxy, heteroaryloxy,        heterocycleoxy, aralkyl lower thioalkyl, heteroaralkyl lower        thioalkyl, heterocycloalkyl lower thioalkyl, heteroaryl lower        alkyl, heterocyclo lower alkyl, heteroarylthio lower alkyl,        arylthio lower alkyl, heterocyclothio lower alkyl,        heteroarylamino lower alkyl, heterocycloamino lower alkyl,        arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, any of which        can be optionally substituted with a moiety that does not        adversely affect the biological properties of the molecule;        —C(O)(CH2)2CO2—M+, —SO3M+, or -lower alkyl-O—R, wherein R is        PO2(OH)—M+, PO3(OH)—M+ or —SO3M+, wherein M+ is a        pharmaceutically acceptable cation; -lower alkylcarbonyl-lower        alkyl; carboxy lower alkyl; -lower alkylamino-lower alkyl;        N,N-di-substituted amino lower alkyl-, wherein the substituents        each independently represent lower alkyl;    -   v) R1 is H, lower alkyl, an optionally substituted carbocycle,        aryl, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl,        alkylheteroaryl or alkylheterocycle;    -   vi) R2 is an optionally substituted alkyl, alkenyl, alkynyl,        aryl, carbocycle, heteroaryl, heterocycle, alkylaryl,        alkylheteroaryl, alkylheteroaryl or alkylheterocycle;    -   vii) alternatively, R22 and R6α or R23 and R6α can join together        to form a bridged carbocycle, aryl, heterocycle or        heteroaromatic;    -   viii) R2α and R3α, R3α and R4α, R4α and R5α, R5α and R6α, R2β        and R3β, R3β and R4β, R4β and R5β or R5β and R6β can        independently join to form a bridged compound selected from the        group consisting of an optionally substituted carbocycle, an        optionally substituted cycloalkenyl, an optionally substituted        cycloalkylcarbonyl, an optionally substituted        cycloalkenylcarbonyl; an optionally substituted aryl, an        optionally substituted heterocylic or an optionally substituted        heteroaromatic, or alkylenedioxy or wherein the ring can include        a carbonyl, cyclic ester, amide, amine, sulfonate, or        phosphonate;    -   ix) at least one of R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β        or R6β is, or R2α and R3α, R3α and R4α, R4α and R5α, R5α and        R6α, R2β and R3β, R3β and R4β, R4β and R5β or R5β and R6β join        together to be, an aryl, heterocycle or heteroaromatic; and    -   x) at least one of R2α, R3α, R4α, R5α, or R6α, and at least one        of R2β, R3β, R4β, R5β or R6β is a substituent other than        hydrogen.

In another embodiment, the compound is of the formula (II):

or its pharmaceutically acceptable salt.

In another embodiment, R1 is independently H or lower alkyl, R2 is anoptionally substituted alkyl; and at least one of R2α, R3α, R4α, R5α, orR6α, and at least one of R2β, R3β, R4β, R5β or R6β is a substituentother than hydrogen.

In another embodiment, R4β or R5β is optionally substituted heteroarylor heterocycle; and at least one of R2α, R3α, R4α, R5α, or R6α is asubstituent other than hydrogen.

In another embodiment, R4α or R5α is optionally substituted heteroarylor heterocycle; and at least one of R2β, R3β, R4β, R5β, or R6β is asubstituent other than hydrogen.

In a particular embodiment, R5β is optionally substituted thienyl orbenzothienyl; R2α, R3α, R4α, R5α, R6α, or R2β, R3β, R4β, and R6β areindependently hydrogen, methoxy, ethoxy, propoxy, benzyloxy,4-carboxybenzyloxy, 4-ethoxycarbonylbenzyloxy, 4-aminobenzyloxy, fluoro,chloro, bromo, iodo, hydroxy, OCH2CO2H, SCH2CO2H, NHCH2CO2H, CO2H,pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, pyrid-4-ylmethoxy;thien-2-ylmethoxy, thien-3-ylmethoxy, fur-2-ylmethoxy, fur-3-ylmethoxyand at least one of R2α, R3α, R4α, R5α, or R6α is a substituent otherthan hydrogen.

In another embodiment, at least one of R2α, R3α, R4α, R5α, R6α, R2β,R3β, R4β, R5β or R6β, is or R2α and R3α, R3α and R4α, R4α and R5α, R5αand R6α, R2β and R3β, R3β and R4β, R4β and R5β or R5β and R6β join toform a carbocycle, aryl, heterocycle or heteroaromatic in which thecarbocycle, aryl, heteroaryl or heterocycle is a 5, 6 or 7 memberedring, optionally conjugated to another carbocycle, aryl, heteroaryl orheterocycle.

In one embodiment, the heteroaryl group is not an oxazole.

In yet another embodiment, either R3α and R4α or R5α and R4α join toform a 5-membered methylendioxyphenyl group.

In one alternative embodiment, one of the A or B rings has only hydrogensubstituents.

While it has been known that certain chalcones exhibit antiinflammatoryproperties, it has not been reported that the presently disclosed classof 1,3-di-(substituted-phenyl)-2-propenones inhibit the expression ofVCAM-1, and are useful anti-inflammatory agents.

One of the challenges of the prior biological use of chalcones has beenthat the phenyl groups of the chalcone can be metabolized by ringhydroxylation (by oxidizing enzymes, including but not limited tocytochrome P450) or via break down of the chalcone double bond. As partof the invention, the present chalcones include a heteroaryl, aryl orheterocyclic group attached to one of the phenyl rings to increase thehalf life and thus bioavailability of the compound. However, theaddition of the heteroaryl, aryl or heterocyclic group can decrease thewater solubility of the compound, which has the effect of actuallylimiting the bioavailability of the compound. Therefore, in a preferredembodiment, the chalcone contains both a heterocycle, heteroaromatic oraryl group on at least one of the A and B phenyl rings to limit themetabolism of the compound, and at least one group that increases thewater solubility of the compound. Since phenyl hydroxylation typicallyoccurs at the para position, in a preferred embodiment, the aryl,heteroaryl or heterocyclic group is positioned at the para position, orat a meta position that blocks para-hydroxylation. Alternatively,halogen, especially fluorine, increases metabolic stability when placedin the position(s) most susceptible to hydroxylation. Bulky alkoxygroups like cyclopropyl methoxy, heteroarylalkoxy (for example, thienylmethoxy, furryl methoxy and pyridyl methoxy) and heterocyclealkoxy alsoincrease metabolic stability when placed at the meta or para position.It has been observed that adding the group that increases watersolubility to the B ring typically increases the water solubility morethan when the same group is added to the A ring, however, this trend maynot hold true in all cases. Preferred water solubilizing groups arealkoxy, such as methoxy, OC(R1)2CO2H, SC(R1)2CO2H, NHC(R1)2CO2H orOC(R1)2CO2H, wherein R1 is H or lower alkyl. In a more generalembodiment, any group that increases the water solubility of thecompound can be used as substituents for R2α, R3α, R4α, R5α, R6α, R2β,R3β, R4β, R5β and R6β, specifically including but not limited to

-   -   alkoxy, alkylthio, alkylamino, aminoalkyl, haloalkylthio, acyl,        amido, acylamino, amino, dialkylamino, aminodialkyl,        trifluoroalkoxy, alkylsulfonyl, haloalkylsulfonyl,        aminocarbonyl, hydroxyl, thiol, cyano, nitro, sulfonic acid,        sulfonate, sulfate, sulfinic acid, sulfenic acid, sulfamide,        sulfonamide, sulfoxide, metal sulfinate, phosphate, phosphonate,        metal phosphonate, phosphinate, alditol, carbohydrate, amino        acid, CO—R2, CO2—R2, polyoxyalkylene, polyol alkyl, NH2.HCl,        oxyalkylamino, alkylcarbonylalkyl, lower alkyl S(O)-lower alkyl,        lower alkyl-S(0)2-lower alkyl; imidazolyl lower alkyl,        morpholinyl lower alkyl, thiazolinyl lower alkyl, piperidinyl        lower alkyl, imidazolylcarbonyl, morpholinyl carbonyl, (lower        alkyl)-aminocarbonyl, N-pyrrylpyridinyl-lower alkyl;        pyridylthio-lower alkyl; morpholinyl-lower alkyl;        hydroxyphenylthio-lower alkyl; cyanophenylthio-lower alkyl;        imidazolylthio-lower alkyl; triazolylthio-lower alkyl;        triazolylphenylthio-lower alkyl; tetrazolylthio-lower alkyl;        tetrazolylphenylthio-lower alkyl; aminophenylthio-lower alkyl;        N,N-di-substituted aminophenylthio-lower alkyl wherein the amine        substituents each independently represent lower alkyl;        amidinophenylthio-lower alkyl; phenylsulfinyl-lower alkyl;        phenylsulfonyl lower alkyl; -lower alkyl-O—R, wherein R is        PO2(OH)—M+ or PO3(OH)—M+ wherein M+ is a pharmaceutically        acceptable cation; —C(O)(CH2)2CO2—M+; —SO3M+; -lower        alkylcarbonyl-lower alkyl; -carboxy lower alkyl; -lower        alkylamino-lower alkyl; N,N-di-substituted amino lower alkyl-,        wherein the substituents each independently represent lower        alkyl; pyridyl-lower alkyl; imidazolyl-lower alkyl;        imidazolyl-Y-lower alkyl wherein Y is thio or amino;        morpholinyl-lower alkyl; pyrrolidinyl-lower alkyl;        thiazolinyl-lower alkyl; piperidinyl-lower alkyl;        morpholinyl-lower hydroxyalkyl; N-pyrryl; piperazinyl-lower        alkyl; N-substituted piperazinyl-lower alkyl, wherein the amine        substituent is lower alkyl; triazolyl-lower alkyl;        tetrazolyl-lower alkyl; tetrazolylamino-lower alkyl; or        thiazolyl-lower alkyl; hydroxyalkyl, aralkoxy, heteroaryl lower        alkoxy, heterocyclo lower alkoxy, heteroaryloxy, heterocycleoxy,        aralkyl lower thioalkyl, heteroaralkyl lower thioalkyl,        heterocycloalkyl lower thioalkyl, heteroaryl lower alkyl,        heterocyclo lower alkyl, heteroarylthio lower alkyl, arylthio        lower alkyl, heterocyclothio lower alkyl, heteroarylamino lower        alkyl, heterocycloamino lower alkyl, arylsulfinyl lower alkyl,        arylsulfonyl lower alkyl, any of which can be optionally        substituted with a moiety that does not adversely affect the        biological properties of the molecule;

In a preferred embodiment, after the target biological activity,metabolic stability and water solubility have been jointly optimized,substituent groups that do not contribute to these factors or contributeanother attribute are removed.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is an illustration of non-limiting examples of compounds of thepresent invention.

FIG. 2 is a bar chart graph of the inhibition of eosinophil recruitment(percent eosinophils in the peritoneal fluid) by 50 mg/kg/dose of3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one.Balb/C mice (n=10) were sensitized to ovalbumin on days 0 and 7 with asubcutaneous injection of ovalbumin absorbed in aluminum hydroxide. Theywere then challenged with an intraperitoneal injection of ovalbumin andsacrificed 48 hrs post-challenge. Peritoneal fluid was then collectedand spun down onto slides. Slides were stained with DiffQuik and adifferential performed. The test compound was administered bysubcutaneously injection −24, −2, +2 and +6 hrs around the time ofovalbumin challenge. This is a model of allergic inflammation aseosinophils are the major leukocyte recruited into the peritoneum.

FIG. 3 is a bar chart graph of the inhibition of paw edema in a mousemodel of delayed type hypersensitivity by 50 mg/kg/dose of3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one.Balb/C mice (n=5) were sensitized intradermally on day 0 with methylatedBSA (metBSA). They were then challenged with metBSA on day 7 in theright hind paw. The animals were sacrificed 24 hours later and the leftand right hind paws weighed. The left hindpaw weight is subtracted fromthe right hind paw to give the paw weight increase. The test compoundwas administered by intraperitoneal injection −24, −2 and +6 hrs aroundthe time of metBSA challenge.

DETAILED DESCRIPTION OF THE INVENTION

It has been discovered that compounds of formula (I) inhibit theexpression of VCAM-1, and thus can be used to treat a patient with adisorder mediated by VCAM-1. These compounds can be administered to ahost as monotherapy, or if desired, in combination with another compoundof formula (I) or another bioloigically active agent, as described inmore detail below.

The compounds can be used to treat inflammatory disorders that aremediated by VCAM-1 including, but not limited to arthritis, asthma,dermatitis, psoriasis, cystic fibrosis, post transplantation late andchronic solid organ rejection, multiple sclerosis, systemic lupuserythematosis, inflammatory bowel diseases, autoimmune diabetes,diabetic retinopathy, rhinitis, ischemia-reperfusion injury,post-angioplasty restenosis, chronic obstructive pulmonary disease(COPD), glomerulonephritis, Graves disease, gastrointestinal allergies,conjunctivitis, atherosclerosis, coronary artery disease, angina andsmall artery disease.

The compounds disclosed herein can be used in the treatment ofinflammatory skin diseases that are mediated by VCAM-1, and inparticular, human endothelial disorders that are mediated by VCAM-1,which include, but are not limited to, psoriasis, dermatitis, includingeczematous dermatitis, and Kaposi's sarcoma, as well as proliferativedisorders of smooth muscle cells.

In yet another embodiment, the compounds disclosed herein can beselected to treat anti-inflammatory conditions that are mediated bymononuclear leucocytes.

In yet another embodiment, the compounds of the present invention can beselected for the prevention or treatment of tissue or organ transplantrejection. Treatment and prevention of organ or tissue transplantrejection includes, but are not limited to treatment of recipients ofheart, lung, combined heart-lung, liver, kidney, pancreatic, skin,spleen, small bowel, or corneal transplants. They are also indicated forthe prevention or treatment of graft-versus-host disease, whichsometimes occurs following bone marrow transplantation.

In an alternative embodiment, the compounds described herein are usefulin both the primary and adjunctive medical treatment of cardiovasculardisease. The compounds are used in primary treatment of, for example,coronary disease states including atherosclerosis, post-angioplastyrestenosis, coronary artery diseases and angina. The compounds can beadministered to treat small vessel disease that is not treatable bysurgery or angioplasty, or other vessel disease in which surgery is notan option. The compounds can also be used to stabilize patients prior torevascularization therapy.

In another aspect the invention provides pharmaceutical compositions forthe treatment of diseases or disorders mediated by VCAM-1 wherein suchcompositions comprise a VCAM-1 inhibiting amount of a chalconederivatives of the formula (I) or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable carrier.

In another aspect the invention provides a method for treating a diseaseor disorder mediated by VCAM-1 comprising administering to a patient aVCAM-1 inhibiting effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

In another aspect the invention provides a method for treatingcardiovascular and inflammatory disorders in a patient in need thereofcomprising administering to said patient an VCAM-1 inhibiting effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

In another aspect the invention provides a method and composition fortreating asthma or arthritis in a patient in need thereof comprisingadministering to said patient an effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof.

I. Compounds of the Present Invention

In one embodiment, the invention provides compounds of formula (I) andtheir pharmaceutically acceptable salts or prodrugs:

or its pharmaceutically acceptable salt, wherein:

-   -   xi) the wavy line indicates that the compound can be in the form        of the E or Z isomer;    -   xii) R22 and R23 are independently hydrogen or (C1-C4)alkyl,    -   xiii) R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β and R6β are        independently    -   xiv) hydrogen, alkyl, carbocycle, aryl, heteroaryl, heterocycle,        aryloxy; arylalkoxy; heteroaryloxy; heteroarylalkoxy,        cycloalkyl, alkoxy, alkylthio, alkylamino, aminoalkyl,        haloalkylthio, acyl, haloalkyl, aryloxy, amido, acylamino,        amino, dialkylamino, aminodialkyl, trifluoroalkoxy,        alkylsulfonyl, haloalkylsulfonyl, aminocarbonyl, alkenyl,        alkynyl, halogen, hydroxyl, thiol, cyano, nitro, sulfonic acid,        sulfonate, sulfate, sulfinic acid, sulfenic acid, sulfamide,        sulfonamide, sulfoxide, metal sulfinate, phosphate, phosphonate,        metal phosphonate, phosphinate, alditol, carbohydrate, amino        acid, OC(R1)2CO2H, SC(R1)2CO2H, NHCHR1CO2H, CO—R2, CO2R1,        polyoxyalkylene, polyol alkyl, oxyalkylamino,        alkylcarbonylalkyl, lower alkyl S(O)-lower alkyl, lower        alkyl-S(O)2-lower alkyl; hydroxyalkyl, aralkoxy, heteroaryl        lower alkoxy, heterocyclo lower alkoxy, heteroaryloxy,        heterocycleoxy, aralkyl lower thioalkyl, heteroaralkyl lower        thioalkyl, heterocycloalkyl lower thioalkyl, heteroaryl lower        alkyl, heterocyclo lower alkyl, heteroarylthio lower alkyl,        arylthio lower alkyl, heterocyclothio lower alkyl,        heteroarylamino lower alkyl, heterocycloamino lower alkyl,        arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, any of which        can be optionally substituted with a moiety that does not        adversely affect the biological properties of the molecule;        —C(O)(CH2)2CO2—M+, —SO3M+, or -lower alkyl-O—R, wherein R is        PO2(OH)—M+, PO3(OH)—M+ or —SO3M+, wherein M+ is a        pharmaceutically acceptable cation; -lower alkylcarbonyl-lower        alkyl; carboxy lower alkyl; -lower alkylamino-lower alkyl;        N,N-di-substituted amino lower alkyl-, wherein the substituents        each independently represent lower alkyl;    -   xv) R1 is H, lower alkyl, an optionally substituted carbocycle,        aryl, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl,        alkylheteroaryl or alkylheterocycle;    -   xvi) R2 is an optionally substituted alkyl, alkenyl, alkynyl,        aryl, carbocycle, heteroaryl, heterocycle, alkylaryl,        alkylheteroaryl, alkylheteroaryl or alkylheterocycle;    -   xvii) alternatively, R22 and R6α or R23 and R6α can join        together to form a bridged carbocycle, aryl, heterocycle or        heteroaromatic;    -   xviii) R2α and R3α, R3α and R4α, R4α and R5α, R5α and R6α, R2β        and R3β, R3β and R4β, R4β and R5β or R5β and R6β can        independently join to form a bridged compound selected from the        group consisting of an optionally substituted carbocycle, an        optionally substituted cycloalkenyl, an optionally substituted        cycloalkylcarbonyl, an optionally substituted        cycloalkenylcarbonyl; an optionally substituted aryl, an        optionally substituted heterocylic or an optionally substituted        heteroaromatic, or alkylenedioxy or wherein the ring can include        a carbonyl, cyclic ester, amide, amine, sulfonate, or        phosphonate;    -   xix) at least one of R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β        or R6β is, or R2α and R3α, R3α and R4α, R4α and R5α, R5α and        R6α, R2β and R3β, R3β and R4β, R4β and R5β or R5β and R6β come        together to be, an aryl, heterocycle or heteroaromatic; and    -   xx) at least one of R2α, R3, R4α, R5α, or R6α, and at least one        of R2β, R3β, R4β, R5β or R6β is a substituent other than        hydrogen.

In another embodiment, the compound is of the formula (II):

or its pharmaceutically acceptable salt.

In another embodiment, R1 is independently H or lower alkyl, R2 is anoptionally substituted alkyl; and at least one of R2α, R3α, R4α, R5α, orR6α, and at least one of R2β, R3β, R4β, R5β or R6β is a substituentother than hydrogen.

In another embodiment, R4β or R5β is optionally substituted heteroarylor heterocycle; and at least one of R2α, R3α, R4α, R5α or R6α is asubstituent other than hydrogen.

In another embodiment, R4α or R5α is optionally substituted heteroarylor heterocycle; and at least one of R2β, R3β, R4β, R5β, or R6β is asubstituent other than hydrogen.

In one alternative embodiment, one of the A or B rings has only hydrogensubstituents.

In a particular embodiment, R5β is optionally substituted thienyl orbenzothienyl; R2α, R3α, R4α, R5α, R6α, or R2β, R3β, R4β, and R6β areindependently hydrogen, methoxy, ethoxy, propoxy, benzyloxy,4-carboxybenzyloxy, 4-ethoxycarbonylbenzyloxy, 4-aminobenzyloxy, fluoro,chloro, bromo, iodo, hydroxy, OCH2CO2H, SCH2CO2H, NHCH2CO2H, CO2H,pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, pyrid-4-ylmethoxy;thien-2-ylmethoxy, thien-3-ylmethoxy, fur-2-ylmethoxy, fur-3-ylmethoxyand at least one of R2α, R3α, R4α, R5α, or R6α is a substituent otherthan hydrogen.

In another embodiment, at least one of R2α, R3α, R4α, R5α, R6α, R2β,R3β, R4β, R5β or R6β, is or R2α and R3α, R3α and R4α, R4α and R5α, R5αand R6α, R2β and R3β, R3β and R4β, R4β and R5β or R5β and R6β join toform a carbocycle, aryl, heterocycle or heteroaromatic in which thecarbocycle, aryl, heteroaryl or heterocycle is a 5, 6 or 7 memberedring, optionally conjugated to another carbocycle, aryl, heteroaryl orheterocycle. In yet another embodiment, either R3α and R4α or R5α andR4α join to form a 5-membered methylendioxyphenyl group.

In a primary embodiment, the compounds of the formula (I) are of themore specific formula (II):

or its pharmaceutically acceptable salt or prodrug thereof, wherein:

-   -   R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β and R6β are defined        above.

In a particular embodiment, the optionally substituted carbocycle, aryl,heteroaryl or heterocycle is a 5, 6 or 7 membered ring, optionallysubstituted or conjugated to another optionally substituted carbocycle,aryl, heteroaryl or heterocycle.

In another sub-embodiment, the invention provides trans compounds offormula (II) and their pharmaceutically acceptable salts or prodrugsthereof wherein;

-   -   R2α, R3α, R4α, R5α and R6α are independently selected from        alkyl, alkoxy, hydroxy, halogen, preferably chloro, heterocycle,        heteroaromatic, OC(R1)2CO2H wherein R1 is H, or lower alkyl,        O-alkylheteroaryl and R2β, R3β, R4β, R5β and R6β are        independently selected from alkyl, alkoxy, hydroxy, halogen,        preferably F or Br, carbocycle, aryl, heterocycle and        heteroaryl, preferably thienyl or benzothienyl.

In one embodiment the invention provides trans compounds of formula (II)and a pharmaceutically acceptable salts or prodrugs that exhibit asufficient solubility in water and an in vitro inhibition of fiftypercent of VCAM expression at 10 micromolar concentration.

In another embodiment, at least one of R2α, R3α, R4α, R5α, R6α, R2β,R3β, R4β, R5β and R6β is selected from halogen, alkoxy, hydroxy,OC(R1)2CO2H, SC(R1)2CO2H, or NHC(R1)2CO2H; or its pharmaceuticallyacceptable salt; R1 is H, or lower alkyl; the remaining Rα/β groups areselected independently from H; halogen, thio, cyano, nitro, optionallysubstituted alkyl; cycloalkyl; hydroxy; alkoxy; alkylthio; alkylamino,aminoalkyl, haloalkylthio; haloalkyl; carboxyl derivatives; aryloxy;arylalkoxy; heteroaryloxy; heteroarylalkoxy, amido; acylamino; amino,dialkylamino; trifluoroalkoxy; alkylsulfonyl, haloalkylsulfonyl;sulfonic acid; sulfonate, sulfate, sulfinic acid, sulfenic acid,sulfamide, sulfonamide; sulfoxide, metal sulfinate, phosphate,phosphonate, metal phosphonate, phosphinate aminocarbonyl; alkenyl;alkynyl; alditol, carbohydrate, carbocycle, aryl, heteroaryl, andheterocycle; or

-   -   the remaining Rα/β groups can join to form a 5, 6 or 7 membered        optionally substituted carbocycle, aryl, heteroaryl or        heterocycle, optionally conjugated to another optionally        substituted carbocycle, aryl, heteroaryl.

In a preferred embodiment the invention provides trans compounds offormula (II) and a pharmaceutically acceptable salts or prodrugs thatincrease the solubility of the molecule while maintaining or increasingthe inhibition of VCAM expression wherein:

-   -   at least one of the R2β, R3β, R4β, R5β and R6β is selected from        OC(R1)2CO2H, SC(R1)2CO2H, NHC(R1)2CO2H or their salts;    -   R2α, R3α, R4α, R5α and R6α are selected independently from H;        halogen, thio, cyano, nitro, optionally substituted alkyl;        cycloalkyl; hydroxy; alkoxy; alkylthio; alkylamino, aminoalkyl,        haloalkylthio; haloalkyl; carboxyl derivatives; aryloxy;        arylalkoxy; heteroaryloxy; heteroarylalkoxy, amido; acylamino;        amino, dialkylamino; trifluoroalkoxy; alkylsulfonyl,        haloalkylsulfonyl; sulfonic acid; sulfonate, sulfate, sulfinic        acid, sulfenic acid, sulfamide, sulfonamide; sulfoxide, metal        sulfinate, phosphate, phosphonate, metal phosphonate,        phosphinate aminocarbonyl; alkenyl; alkynyl; alditol,        carbohydrate, carbocycle, aryl, heteroaryl and heterocycle; or    -   the remaining Rα/β groups can join to form a 5, 6 or 7 membered        optionally substituted carbocycle, aryl, heteroaryl or        heterocycle, optionally conjugated to another optionally        substituted carbocycle, aryl, heteroaryl.

In yet another preferred embodiment the invention provides transcompounds of formula (II) and a pharmaceutically acceptable salts orprodrugs that increase the solubility of the molecule while maintainingor increasing the inhibition of VCAM expression wherein:

-   -   R2β is selected from OC(R1)2CO2H, SC(R1)2CO2H, or NHC(R1)2CO2H;        or its pharmaceutically acceptable salt;    -   R1 is H, or lower alkyl;    -   R3β, R4β, R5β, R6β, R2α, R3α, R4α, R5α and R6α are selected        independently from H; halogen, thio, cyano, nitro, optionally        substituted alkyl; cycloalkyl; hydroxy; alkoxy; alkylthio;        alkylamino, aminoalkyl, haloalkylthio; thio; cyano; halo;        haloalkyl; nitro; carboxyl derivatives; aryloxy; arylalkoxy;        heteroaryloxy; heteroarylalkoxy, amido; acylamino; amino,        dialkylamino; trifluoroalkoxy; alkylsulfonyl, haloalkylsulfonyl;        sulfonic acid; sulfonate, sulfate, sulfinic acid, sulfenic acid,        sulfamide, sulfonamide; sulfoxide, metal sulfinate, phosphate,        phosphonate, metal phosphonate, phosphinate aminocarbonyl;        alkenyl; alkynyl; alditol, carbohydrate, carbocycle, aryl,        heteroaryl, and heterocycle; or    -   R2α and R3α, R3α and R4α, R4α and R5α, R5α and R6α, R3β and R4β,        R4β and R5β or R5β and R6β can join to form a 5, 6 or 7 membered        optionally substituted carbocycle, aryl, heteroaryl or        heterocycle, optionally conjugated to another optionally        substituted carbocycle, aryl, heterocycle or heteroaryl.

In yet another embodiment the invention provides compounds of theformula (II) and a pharmaceutically acceptable salts or prodrugs thatare metabolically stable:

wherein:

-   -   R4α and R4β are independently selected from cyano; halo; nitro;        substituted or unsubstituted alkyl; cycloalkyl; alkoxy;        alkylthio; alkylamino; aminoalkyl; haloalkylthio; haloalkyl;        carboxyl derivatives; aryloxy; arylalkoxy; heteroaryloxy;        heteroarylalkoxy, amido; acylamino; amino, dialkylamino;        trifluoroalkoxy; aminocarbonyl; alkenyl; alkynyl; alditol;        carbohydrate; aryl; heteroaryl; and heterocycle; or    -   R2α and R4α; R4α and R5α; R3β and R4β; or R4β and R5β;        independently form a 5-7 membered optionally substituted        carbocyclic, aryl; heteroaryl or heterocyclic ring;    -   the remaining Rα/β groups are selected independently from H;        halogen, thio, cyano, nitro, optionally substituted alkyl;        cycloalkyl; hydroxy; alkoxy; alkylthio; alkylamino, aminoalkyl,        haloalkylthio; haloalkyl; carboxyl derivatives; aryloxy;        arylalkoxy; heteroaryloxy; heteroarylalkoxy, amido; acylamino;        amino, dialkylamino; trifluoroalkoxy; alkylsulfonyl,        haloalkylsulfonyl; sulfonic acid; sulfonate, sulfate, sulfinic        acid, sulfenic acid, sulfamide, sulfonamide; sulfoxide, metal        sulfinate, phosphate, phosphonate, metal phosphonate,        phosphinate aminocarbonyl; alkenyl; alkynyl; alditol,        carbohydrate, carbocycle, aryl, heteroaryl and heterocycle; or    -   the remaining Rα/β groups can join to form a 5, 6 or 7 membered        optionally substituted carbocycle, aryl, heteroaryl or        heterocycle, optionally conjugated to another optionally        substituted carbocycle, aryl, heteroaryl, and    -   R1 is H; or lower alkyl; or

In a preferred embodiment the invention provides trans compounds offormula (II) and a pharmaceutically acceptable salts or prodrugs thatare metabolically stable:

wherein:

-   -   R4α and R4β independently from each other are selected from        halogen preferably F or heteroaryl preferably thienyl and        benzothienyl and, and R3β, R5β, R6β, R2α, R3α, R5α and R6α are        selected from H, cyano; nitro; halo preferably F; optionally        substituted alkyl; cycloalkyl; alkoxy; alkylthio; alkylamino;        aminoalkyl; haloalkylthio; haloalkyl; carboxyl derivatives;        aryloxy; amido; acylamino; amino, dialkylamino; trifluoroalkoxy;        aminocarbonyl; alkenyl; alkynyl; alditol; carbohydrate; aryl;        heteroaryl; and heterocycle; or    -   R3α and R4α, R4α and R5β, R3β and R4β, or R4β and R5β        independently can join to form a 5-7 membered optionally        substituted carbocylic; aryl; heteroaryl; or heterocyclic ring;        and    -   the remaining Rα/β groups are selected independently from H;        halogen, thio, cyano, nitro, optionally substituted alkyl;        cycloalkyl; hydroxy; alkoxy; alkylthio; alkylamino, aminoalkyl,        haloalkylthio; haloalkyl; carboxyl derivatives; aryloxy;        arylalkoxy; heteroaryloxy; heteroarylalkoxy, amido; acylamino;        amino, dialkylamino; trifluoroalkoxy; alkylsulfonyl,        haloalkylsulfonyl; sulfonic acid; sulfonate, sulfate, sulfinic        acid, sulfenic acid, sulfamide, sulfonamide; sulfoxide, metal        sulfinate, phosphate, phosphonate, metal phosphonate,        phosphinate aminocarbonyl; alkenyl; alkynyl; alditol,        carbohydrate, carbocycle, aryl, heteroaryl and heterocycle; or    -   the remaining Rα/β groups can join to form a 5, 6 or 7 membered        optionally substituted carbocycle, aryl, heteroaryl or        heterocycle, optionally conjugated to another optionally        substituted carbocycle, aryl, heteroaryl, and    -   R1 is H; or lower alkyl.

In another embodiment the invention provides trans compounds of formula(II) and a pharmaceutically acceptable salts or prodrugs:

wherein:

-   -   at least one of the following pairs R3α and R4α, R4α and R5α,        R3β and R4β, or R4β and R5β comes together to form a 5, 6 or 7        membered optionally substituted heteroaryl or optionally        substituted heterocycle, optionally conjugated to another        optionally substituted carbocycle, optionally substituted aryl,        or heteroaryl, wherein the heteroatom of the ring is selected        from O, S or N; and    -   the remaining Rα/β groups are independently selected from H;        halogen, thio, cyano, nitro, optionally substituted alkyl;        cycloalkyl; hydroxy; alkoxy; alkylthio; alkylamino, aminoalkyl,        haloalkylthio; haloalkyl; carboxyl derivatives; aryloxy;        arylalkoxy; heteroaryloxy; heteroarylalkoxy, amido; acylamino;        amino, dialkylamino; trifluoroalkoxy; alkylsulfonyl,        haloalkylsulfonyl; sulfonic acid; sulfonate, sulfate, sulfinic        acid, sulfenic acid, sulfamide, sulfonamide; sulfoxide, metal        sulfinate, phosphate, phosphonate, metal phosphonate,        phosphinate aminocarbonyl; alkenyl; alkynyl; alditol,        carbohydrate, carbocycle, aryl, heteroaryl and heterocycle; or    -   the remaining Rα/β groups can join to form a 5, 6 or 7 membered        optionally substituted carbocycle, aryl, heteroaryl or        heterocycle, optionally conjugated to another optionally        substituted carbocycle, aryl, heteroaryl.

In another embodiment, the invention provides trans compounds of formula(II) and their pharmaceutically acceptable salts or prodrugs thereof:

wherein;

-   -   R2α, R3α, R4α, R5α and R6α are independently selected from        alkyl, alkoxy, halogen, preferably Cl, Br or I, heteroaryl,        O-alkylheterocycle, O-akylheteroaryl, carboxyalkyl;    -   R2β, R3β, R4β, R5β and R6β are independently selected from        alkyl, alkoxy, halogen, preferably F or Br, or heteroaryl,        preferably benzothienyl.

In one preferred embodiment, the invention provides trans compounds offormula (II) and their pharmaceutically acceptable salts or prodrugsthereof:

wherein:

-   -   R3β and R6β are independently H;    -   R2α, R3α, R4α, R5α and R6α are independently selected from H,        OH, OR (R is lower alkyl), halogen, OC(R1)2CO2H, SC(R1)2CO2H, or        NHC(R1)2CO2H; or its pharmaceutically acceptable salt;    -   R2β, R4β and R5β are independently selected from O-alkyl,        OC(R1)2CO2H, SC(R1)2CO2H, or NHC(R1)2CO2H; or its        pharmaceutically acceptable salt; and    -   R1 is H, or lower alkyl.

In another preferred embodiment, the invention provides trans compoundsof formula (II) and their pharmaceutically acceptable salts or prodrugsthereof:

wherein:

-   -   R2α, R6β, R3β and R6β are H;    -   R3α , R5β, R3β and R6β are OMe;    -   R4α is OC(R1)2CO2H, CO2H, SC(R1)2CO2H or NHC(R1)2CO2H; or its        pharmaceutically acceptable salt;    -   R1 is H or lower alkyl; and    -   R5β is a heteroaryl or heterocycle.

In another preferred embodiment, the invention provides trans compoundsof formula (II) and their pharmaceutically acceptable salts or prodrugsthereof:

wherein;

-   -   R2α, R6α, R3β and R6β are H;    -   R3α, R4α, R5α and R4β are OMe;    -   R2β is selected from OC(R1)2CO2H, CO2H, SC(R1)2CO2H or        NHC(R1)2CO2H; or its pharmaceutically acceptable salt;    -   R1 is H or lower alkyl; and    -   R5β is a heteroaryl or heterocycle.

In another preferred embodiment, the invention provides trans compoundsof formula (II) and their pharmaceutically acceptable salts or prodrugsthereof:

wherein;

-   -   R2α, R6α, R3β and R6β are H;    -   R3α, R4α, R5α, R2β and R4β are OMe; and    -   R5β is a heteroaryl or heterocycle.

In another preferred embodiment, the invention provides trans compoundsof formula (II) and their pharmaceutically acceptable salts or prodrugsthereof:

wherein;

-   -   R2α, R6α, R2β and R6β are H;    -   R3α, R4α, R5β, R3β and R4β are OMe; and    -   R5β is a heteroaryl or heterocycle.

In another preferred embodiment, the invention provides trans compoundsof formula (II) and their pharmaceutically acceptable salts or prodrugsthereof:

wherein;

-   -   R3β and R6β are H;    -   R2β and R4β are OMe and,    -   R2α, R3α, R4α , R5α and R6α are independently selected from H,        OH, SH, halo, alkyl, CF3, O-alkyl, CO2H, NH2, aminoalkyl,        aminodialkyl, SO3H, sulfonamine, sulfonaminodi- and mono-alkyl,        α-aminoacid, heterocycle, OC(R1)2CO2H, CO2H, SC(R1)2CO2H or        NHC(R1)2CO2H; or its pharmaceutically acceptable salt;    -   R1 is H or lower alkyl; and    -   R5β is a heteroaryl.

In another preferred embodiment, the invention provides trans compoundsof formula (II) and their pharmaceutically acceptable salts or prodrugsthereof:

wherein;

-   -   R3β, R5β and R6β are H;    -   R4β is OMe and,    -   R2β is OC(R1)2CO2H, CO2H, SC(R1)2CO2H or NHC(R1)2CO2H; or its        pharmaceutically acceptable salt;    -   R2α, R3α, R4α, R5α and R6α are independently selected from H,        OH, SH, halo, alkyl, CF3, O-alkyl, CO2H, NH2, aminoalkyl,        aminodialkyl, SO3H, sulfonamine, sulfonaminodi- and mono-alkyl,        α-aminoacid, heterocycle, heteroaryl, OC(R1)2CO2H, SC(R1)2CO2H,        or NHC(R1)2CO2H; or its pharmaceutically acceptable salt; and    -   R1 is H, or lower alkyl.

In yet another preferred embodiment, the invention provides transcompounds of formula (II) and their pharmaceutically acceptable salts orprodrugs thereof:

wherein;

-   -   R2α and R6α are H and,    -   R4β, R3α, R4α and R5α are OMe and, R2β is OC(R1)2CO2H,        SC(R1)2CO2H, or NHC(R1)2CO2H; or its pharmaceutically acceptable        salt;    -   R3β, R5β and R6β are independently selected from H, OH, SH,        halo, alkyl, CF3, O-alkyl, CO2H, NH2, aminoalkyl, aminodialkyl,        SO3H, sulfonamine, sulfonaminodi- and mono-alkyl, α-aminoacid,        heterocycle, heteroaryl, OC(R1)2CO2H, SC(R1)2CO2H, or        NHC(R1)2CO2H; or its pharmaceutically acceptable salt; and    -   R1 is H, or lower alkyl.

In yet another preferred embodiment, the invention provides transcompounds of formula (II) and their pharmaceutically acceptable salts orprodrugs thereof:

wherein;

-   -   R2α, and R6α are independently H and,    -   R4β, R3α, R4α, R5α and R6α are OMe and,    -   R3β, R5β and R6β are independently selected from H, OH, SH,        halo, alkyl, CF3, O-alkyl, CO2H, NH2, aminoalkyl, aminodialkyl,        SO3H, sulfonamine, sulfonaminodi- and mono-alkyl, α-aminoacid,        heterocycle, heteroaryl, C(R1)2CO2H, OC(R1)2CO2H, SC(R1)2CO2H,        or NHC(R1)2CO2H; or its pharmaceutically acceptable salt;    -   R1 is H, or lower alkyl.

In yet another preferred embodiment, the invention provides transcompounds of formula (II) and their pharmaceutically acceptable salts orprodrugs thereof:

wherein;

-   -   R2α and R6α are H and,    -   R3β, R4β, R3α, R4α and R5α are OMe and,    -   R2β, R5β and R6β are independently selected from H, OH, SH,        halo, alkyl, CF3, O-alkyl, CO2H, NH2, aminoalkyl, aminodialkyl,        SO3H, sulfonamine, sulfonaminodi- and mono-alkyl, α-aminoacid,        heterocycle, heteroaryl, C(R1)2CO2H, OC(R1)2CO2H, SC(R1)2CO2H,        or NHC(R1)2CO2H; or its pharmaceutically acceptable salt;    -   R1 is H, or lower alkyl.

In yet another embodiment, the invention provides trans compounds offormula (II) and their pharmaceutically acceptable salts or prodrugsthereof:

wherein;

-   -   R3β, R4β and R6β are H;    -   R4β is OMe and,    -   R2β is C(R1)2CO2H, OC(R1)2CO2H, SC(R1)2CO2H, or NHC(R1)2CO2H; or        its pharmaceutically acceptable salt;    -   R2α-R6α are independently selected from H, OH, SH, halo, alkyl,        CF3, O-alkyl, CO2H, NH2, aminoalkyl, aminodialkyl, sulfonic        acid, sulfonamine, sulfonaminodi- and mono-alkyl, α-amrinoacid,        heterocycle, heteroaryl, C(R1)2CO2H, OC(R1)2CO2H, SC(R1)2CO2H,        or NHC(R1)2CO2H; or its pharmaceutically acceptable salt;    -   R1 is H, or lower alkyl.

In yet another embodiment, the invention provides trans compounds offormula (II) and their pharmaceutically acceptable salts or prodrugsthereof:

wherein;

-   -   R3β, R5β and R6β are H;    -   R2β and R4β are OMe;    -   R2α-R6α are independently selected from H, OH, SH, halo, alkyl,        CF3, O-alkyl, CO2H, NH2, aminoalkyl, aminodialkyl, sulfonic        acid, sulfonamine, sulfonaminodi- and mono-alkyl, α-aminoacid,        heterocycle, heteroaryl, C(R1)2CO2H, OC(R1)2CO2H, SC(R1)2CO2H,        or NHC(R1)2CO2H; or its pharmaceutically acceptable salt;    -   R1 is H, or lower alkyl.

In yet another embodiment, the invention provides trans compounds offormula (II) and their pharmaceutically acceptable salts or prodrugsthereof:

wherein;

-   -   R2β, R5β and R6β are H;    -   R3β and R4β are OMe;    -   R2α-R6α are independently selected from H, OH, SH, halo, alkyl,        CF3, O-alkyl, CO2H, NH2, aminoalkyl, aminodialkyl, sulfonic        acid, sulfonamine, sulfonaminodi- and mono-alkyl, α-aminoacid,        heterocycle, heteroaryl, C(R1)2CO2H, OC(R1)2CO2H, SC(R1)2CO2H,        or NHC(R1)2CO2H; or its pharmaceutically acceptable salt;    -   R1 is H, or lower alkyl.

In yet another embodiment, the invention provides trans compounds offormula (II) and their pharmaceutically acceptable salts or prodrugsthereof:

wherein;

-   -   R2α, R3α and R6α are H;    -   R4β is OMe and,    -   R4α and R5α together form a five or six membered substituted        heterocylic ring and,    -   R2 is OC(R1)2CO2H, SC(R1)2CO2H, or NHC(R1)2CO2H; or its        pharmaceutically acceptable salt;    -   R3β, R5β and R6β are independently selected from H, OH, SH,        halo, alkyl, CF3, O-alkyl, CO2H, NH2, aminoalkyl, aminodialkyl,        sulfonic acid, sulfonamine, sulfonaminodi- and mono-alkyl,        α-aminoacid, heterocycle, heteroaryl, C(R1)2CO2H, OC(R1)2CO2H,        SC(R1)2CO2H, or NHC(R1)2CO2H; or its pharmaceutically acceptable        salt; and    -   R1 is H, or lower alkyl.

In yet another embodiment, the invention provides trans compounds offormula (II) and their pharmaceutically acceptable salts or prodrugsthereof:

wherein;

-   -   R2α, R3α and R6α are H;    -   R4α and R5α together form a five or six membered substituted        heterocylic ring;    -   R2β and R4β are methoxy;    -   R3β, R5β and R6β are independently selected from H, OH, SH,        halo, alkyl, CF3, O-alkyl, CO2H, NH2, aminoalkyl, aminodialkyl,        sulfonic acid, sulfonamine, sulfonaminodi- and mono-alkyl,        α-aminoacid, heterocycle, heteroaryl, C(R1)2CO2H, OC(R1)2CO2H,        SC(R1)2CO2H, or NHC(R1)2CO2H; or its pharmaceutically acceptable        salt; and    -   R1 is H, or lower alkyl.

In yet another embodiment, the invention provides trans compounds offormula (II) and their pharmnaceutically acceptable salts or prodrugsthereof:

wherein;

-   -   R2α, R2α and R6α are H;    -   R4α and R5α together form a five or six membered substituted        heterocylic ring;    -   R3β and R4β are methoxy;    -   R2β, R5β and R6β are independently selected from H, OH, SH,        halo, alkyl, CF3, O-alkyl, CO2H, NH2, aminoalkyl, aminodialkyl,        SO3H, sulfonamine, sulfonaminodi- and mono-alkyl, α-aminoacid,        heterocycle, heteroaryl, C(R1)2CO2H, OC(R1)2CO2H, SC(R1)2CO2H,        or NHC(R1)2CO2H; or its pharmaceutically acceptable salt; and    -   R1 is H, or lower alkyl.

In yet another embodiment, the invention provides trans compounds offormula (II) and their pharmaceutically acceptable salts or prodrugsthereof:

wherein;

-   -   R3β and R6β are H;    -   R2β is methoxy and,    -   R4β is selected from OC(R1)2CO2H, SC(R1)2CO2H, or NHC(R1)2CO2H;        or its pharmaceutically acceptable salt;    -   R2α-6α are independently selected from H, OH, SH, halo, alkyl,        CF3, O-alkyl, CO2H, NH2, aminoalkyl, aminodialkyl, sulfonic        acid, sulfonamine, sulfonaminodi- and mono-alkyl, α-aminoacid,        heterocycle, heteroaryl, C(R1)2CO2H, OC(R1)2CO2H, SC(R1)2CO2H,        or NHC(R1)2CO2H; or its pharmaceutically acceptable salt;    -   R1 is H, or lower alkyl.

In yet another embodiment, the invention provides trans compounds offormula (II) and their pharmaceutically acceptable salts or prodrugsthereof:

wherein;

-   -   R3β, R6α and R6β are H;    -   R4β is OMe;    -   R2β is selected from OC(R1)2CO2H, SC(R1)2CO2H, or NHC(R1)2CO2H;        or its pharmaceutically acceptable salt;    -   R1 is H, or lower alkyl; and    -   (R2α and R3α), (R3α and R4α) or (R4α and R5α) join to form a 5        or 6 membered optionally substituted heteroaryl or heterocycle,        or optionally conjugated to another optionally substituted        carbocycle, aryl, or heteroaryl.

In yet another embodiment the invention provides trans compounds offormula (II) and a pharmaceutically acceptable salts or prodrugs:

wherein;

-   -   R5β is heteroaryl preferably 2-benzothienyl and, 2-thienyl and,    -   R2β and R4β are independently H, or OMe and,    -   R3β and R6β and R6α are H and,    -   R2α, R3α, R4α and R5α are independently H, OH, alkoxy, halo,        heteroaryl group, or OCHR1CO2H; or its pharmaceutically        acceptable salt; and    -   R1 is H, or lower alkyl.

In another preferred embodiment the invention provides trans compoundsof formula (II) and a pharmaceutically acceptable salts or prodrugs:

wherein;

-   -   R4α is alkoxy, halo, preferably F, OC(R1)2CO2H, SC(R1)2CO2H, or        NHC(R1)2CO2H; or its pharmaceutically acceptable salt;    -   R1 is H, or lower alkyl, preferably methyl;    -   R2α, R6α, R3β and R6β are H and,    -   R3α, R5α, R2β and R4β are selected from electron donating groups        including but not limited to amino, thiol, alkylthio, alkoxy,        preferably OMe;    -   R5β is an heteroaryl including furanyl, pyrrolyl, thienyl or        pyridinyl, but preferably benzothienyl.

In another preferred embodiment the invention provides trans compoundsof formula (II) and a pharmaceutically acceptable salts or prodrugs:

wherein;

-   -   R2β is H, alkoxy, hydroxyl, OC(R1)2CO2H, SC(R1)2CO2H, or        NHC(R1)2CO2H; or its pharmaceutically acceptable salt;    -   R1 is H, or lower alkyl, preferably Me; R4β, R5α and R2α are        independently hydroxy or alkoxyl, preferably methoxy;    -   R2α, R6α, R3β and R6β are independently H; and R4α is hydroxy,        alkoxy or halogen, preferably F.

In another preferred embodiment the compounds of the formula (II) and apharmaceutically acceptable salts or prodrugs:

wherein;

-   -   R2β is H, hydroxy, alkoxy, OC(R1)2CO2H, SC(R1)2CO2H, or        NHC(R1)2CO2H; or its pharmaceutically acceptable salt;    -   R1 is H, or lower alkyl, preferably methyl; R4β and R3α are        independently hydroxyl or alkoxy, preferably methoxy;    -   R2α, R6α, R3α and R6β are H;    -   R5β is heteroaryl, preferably 2-thienyl or 2-benzo[b]thienyl;        and    -   R4α and R5α join to form a 5, 6 or 7 membered optionally        substituted carbocycle, aryl, heteroaryl or heterocycle,        optionally conjugated to another optionally substituted        carbocycle, aryl, or heteroaryl.

In another preferred embodiment the trans compounds of the formula (II)and a pharmaceutically acceptable salts or prodrugs:

wherein;

-   -   R3α, R5α, R6α, R2β, R5β and R6β are H;    -   R2α, R3β and R4β are independently halo, preferably F, hydroxyl        or alkoxy, preferably methoxy; and    -   R4α is an heteroaryl preferably 2-thienyl.

In another preferred embodiment the trans compounds of formula (II) anda pharmaceutically acceptable salts or prodrugs:

wherein;

-   -   R3α, R5α, R6α, R2β and R4β are independently hydroxy or alkoxy,        preferably methoxy;    -   R2α, R6α, R3β and R6α are H;    -   R4α is OC(R1)2heterocycle or its pharmaceutically acceptable        salt;    -   R1 is H, or lower alkyl; and    -   R5β is heteroaryl preferably benzo[b]thienyl.

In another alternative embodiment the trans compounds of formula (II)and a pharmaceutically acceptable salts or prodrugs:

wherein;

-   -   at least one of R3α, R4α, R4β, or R5β is selected from a group        consisting of the moieties in the following table (1):

TABLE 1

and the remaining Rα/β groups are selected independently from H;halogen, thio, cyano, nitro, optionally substituted alkyl; cycloalkyl;hydroxy; alkoxy; alkylthio; alkylamino, aminoalkyl, haloalkylthio;haloalkyl; carboxyl derivatives; aryloxy; arylalkoxy; heteroaryloxy;heteroarylalkoxy, amido; acylamino; amino, dialkylamino;trifluoroalkoxy; alkylsulfonyl, haloalkylsulfonyl; sulfonic acid;sulfonate, sulfate, sulfinic acid, sulfenic acid, sulfamide,sulfonamide; sulfoxide, metal sulfinate, phosphate, phosphonate, metalphosphonate, phosphinate aminocarbonyl; alkenyl; alkynyl; alditol,carbohydrate, carbocycle, aryl, heteroaryl and heterocycle; or

-   -   the remaining Rα/β groups can join to form a 5, 6 or 7 membered        optionally substituted carbocycle, aryl, heteroaryl or        heterocycle, optionally fused to another optionally substituted        carbocycle, aryl, heteroaryl, or heterocycle.

Examples of active chalcone derivatives prepared in this invention arelisted in Table 2.

TABLE 2

X Z 4-carboxymethoxy-3,5- 2,4-dimethoxy-5-(benzo[b]thien-2- dimethoxy,sodium salt yl) 2,4,6-trimethoxy 2,4-difluoro 2,3-dichloro-4-methoxy5-bromo-2-methoxy 2,4,6-trimethoxy 4-hydroxy-3,5-dimethoxy3,5-dimethoxy-4-(4- 3,4,5-trimethoxy methoxybenzyloxy) 3,4,5-trimethoxy5-bromo-2-methoxy 2,3,4-trimethoxy 3-bromo-4,5-dimethoxy3,4,5-trimethoxy 3,4-dimethoxy-5-phenyl 4-hydroxy-3,5-dimethoxy2,4-dimethoxy-5-(benzo[b]thien-2- yl) 4-carboxymethoxy-3,5-2,4-dimethoxy-5-(benzo[b]thien-2- dimethoxy yl) 2,3,4-trimethoxy5-(benzo[b]thien-2-yl)-3,4- dimethoxy 3,4,5-trimethoxy2-methoxy-5-(4-methylthien-2-yl) 3,4-dimethoxy2-methoxy-5-(5-methylthien-2-yl) 3,4,5-trimethoxy2-methoxy-5-(5-methylthien-2-yl) 3,5-dimethoxy-4-(1,4- 3,4,5-trimethoxybenzodioxan-3-methoxy) 2,5-dimethoxy 2-methoxy-5-(thien-2-yl)3,4,5-trimethoxy 3,4-dimethoxy-5-(thien-2-yl) 3,4-dichloro-2-hydroxy,sodium 2-methoxy-5-(thien-2-yl) salt 3,4-dimethoxy2-methoxy-5-(4-methylthien-2-yl) 3,4,5-trimethoxy3,4-dimethoxy-5-(3-pyridyl) 3,4,5-trimethoxy2,4-dimethoxy-5-(thien-2-yl) 3,4,5-trimethoxy 5-bromo-2,4-dimethoxy3,5-dimethoxy 2-methoxy-5-(thien-2-yl) 4-iodo-2-methoxy2-methoxy-5-(thien-2-yl) 4-(3,4-dimethoxybenzyloxy)-3- 3,4,5-trimethoxymethoxy 4-(3,4-dimethoxybenzyloxy)- 3,4,5-trimethoxy 3,5-dimethoxy2,4,5-trimethoxy 3,4,5-trimethoxy 3,4,5-trimethoxy 2-bromo-4,5-dimethoxy3,4-dichloro-2-hydroxy 5-bromo-2-methoxy 3-methoxy-4-(3,4,5-3,4,5-trimethoxy trimethoxybenzyloxy) 3-methoxy-4-(4-2-methoxy-5-(thien-2-yl) pyridylmethoxy), hydrogen chloride3-methoxy-4-(2- 2-methoxy-5-(thien-2-yl) pyridylmethoxy), hydrogenchloride 2-methoxy-4-(thien-2-yl) 3,4-difluoro 3,4,5-trimethoxy5-(benzo[b]thien-2-yl)-2-methoxy 3,4-dichloro-2-hydroxy2-methoxy-5-(thien-2-yl) 3,4-dimethoxy 5-(benzo[b]thien-2-yl)-2-methoxy2,3,4-trimethoxy 2,4-dimethoxy-5-(thien-2-yl) 3-methoxy-4-(2-2-methoxy-5-(thien-2-yl) pyridylmethoxy) 4-(fur-2-ylmethoxy)-3,5-3,4,5-trimethoxy dimethoxy 4-iodo-2-methoxy 3,4,5-trimethoxy2,4,6-trimethoxy 3-bromo-4,5-dimethoxy 3,4-methylenedioxy2-methoxy-5-(5-methylthien-2-yl) 4-hydroxy-3,5-dimethoxy,2,4-dimethoxy-5-(benzo[b]thien-2- sodium salt yl) 3-methoxy-4-(3-2-methoxy-5-(thien-2-yl) pyridylmethoxy) 4-methoxy5-(benzo[b]thien-2-yl)-2-methoxy 3,5-dimethoxy-4-(3,4- 3,4,5-trimethoxymethylenedioxybenzyloxy) 3,5-dimethoxy-4-(thien-2- 3,4,5-trimethoxyylmethoxy) 3,4,5-trimethoxy 3-fluoro-4-methoxy 3,4-dimethoxy3-bromo-4,5-dimethoxy 2,3,4-trimethoxy 3,4-dimethoxy-5-(thien-2-yl)3,5-dimethoxy-4-(3,4,5- 3,4,5-trimethoxy trimethoxybenzyloxy)3,4,5-trimethoxy 5-(5-acetylthien-2-yl)-3,4- dimethoxy 4-methoxy2-methoxy-5-(thien-2-yl) 2,6-dimethoxy 2-methoxy-5-(thien-2-yl)3,4-dimethoxy 2-methoxy-5-(thien-2-yl) 2,4,6-trimethoxy2-methoxy-5-(thien-2-yl) 3,4,5-trimethoxy 2-methoxy-5-(thien-2-yl)5-(2,4-dimethoxyphenyl) 3,4,5-trimethoxy 2-bromo-4,5-dimethoxy2-bromo-4,5-dimethoxy 3,4,5-trimethoxy 4-hydroxy 3-methoxy-4-(4-3,4,5-trimethoxy methoxybenzyloxy) 4-(4-ethoxycarbonyl-2-methoxy-5-(thien-2-yl) benzyloxy)-3-methoxy4-(2,3-isopropylidenedioxy-1- 5-(benzo[b]thien-2-yl)-2,4-propoxy)-3,5-dimethoxy dimethoxy 3-methoxy-4-(4-2-methoxy-5-(thien-2-yl) pyridylmethoxy) 4-(3-acetylphenyl)-2-methoxy3,4,5-trimethoxy 3,4,5-trimethoxy 3-bromo-4,5-dimethoxy3,4-methylenedioxy 5-bromo-2-methoxy 3,4-methylenedioxy2-methoxy-5-(thien-2-yl) 3,4-methylenedioxy2-methoxy-5-(4-methylthien-2-yl) 2-methoxy-5-(thien-2-yl)4-ethoxy-3-fluoro 3,4,5-trimethoxy 5-(benzo[b]thien-2-yl)-2-carboxymethoxy-4-methoxy, sodium salt 3,4,5-trimethoxy5-(benzo[b]thien-2-yl)-3,4- dimethoxy 3,4,5-trimethoxy5-(benzo[b]thien-2-yl)-2,4- dimethoxy 4-(4-carboxybenzyloxy)-3-2-methoxy-5-(thien-2-yl) methoxy 3,5-dimethoxy-4-(2- 3,4,5-trimethoxymethoxyethoxy) 2,3,4-trimethoxy 5-(4-formylphenyl)-3,4-dimethoxy2,4-dimethoxy 4-trifluoromethyl 3,4-difluoro 2-methoxy-5-(thien-2-yl)3,4,5-trimethoxy hydrogen 4-(3-chlorophenyl) 3,4,5-trimethoxy3,4,5-trimethoxy 4-(thien-2-yl) 5-(3-chlorophenyl)-2,4- 3,4,5-trimethoxydimethoxy 4-(4-aminobenzyloxy)-3- 2-methoxy-5-(thien-2-yl) methoxy3-methoxy-4-(3,4- 3,4,5-trimethoxy methylenedioxybenzyloxy)4-hydroxy-3-methoxy 2-methoxy-5-(thien-2-yl) 2,3,4-trimethoxy5-(benzo[b]thien-2-yl)-2,4- dimethoxy 3,4,5-trimethoxy5-(benzo[b]thien-2-yl)-2- carboxymethoxy-4-methoxy3,5-di-tert-butyl-4-methoxy hydrogen 3,5-dimethoxy-4-(2-5-(benzo[b]thien-2-yl)-2,4- morpholinoethoxy) dimethoxy 2-methoxy-4-(3-2-methoxy-5-(thien-2-yl) methoxyphenyl) 3,4-dimethoxy5-(benzo[b]thien-2-yl)-2,4- dimethoxy 3,4,5-trimethoxy 4-bromo2,5-dimethoxy-4-(thien-2-yl- 2-methoxy-5-(thien-2-yl) methoxy)3,4-dimethoxy 4-(thien-2-yl) 2,4-dihydroxy 4-hydroxy5-bromo-2,4-dimethoxy 3,4,5-trimethoxy 2,4,5-triethoxy3-bromo-4,5-dimethoxy 4-methoxy 3,4-dimethoxy 2-methoxy-4-(thien-2-yl)2-methoxy-4-(thien-2-yl) 3,5-di-tert-butyl-4-methoxy 4-methoxy hydrogenhydrogen 4-fluoro 4-fluoro hydrogen 4-nitro 4-methoxy hydrogen3,4-dichloro-2-hydroxy 5-(benzo[b]thien-2-yl)-2-methoxy 3-chlorohydrogen 3,5-di-tert-butyl-4-hydroxy 4-methoxy 4-methyl3,5-di-tert-butyl-4-hydroxy hydrogen 3,5-di-tert-butyl-4-hydroxy3-methoxy-4-(4-tert-butyloxy- 2-methoxy-5-(thien-2-yl)carbonylaminobenzyloxy) hydrogen 2,4,6-triisopropyl 4-bromo3,4,5-trimethoxy 4-benzyloxy-3,5-dimethoxy 3-bromo-4,5-dimethoxy

5-(benzo[b]thien-2-yl)-2,4- dimethoxy

Alternative embodiments include the compounds illustrated below, ortheir pharmaceutically acceptable salts, wherein the variables are asdefined above.

wherein Y is a phenyl ring conjugated to another heteroaromatic orheterocycle.

In yet another embodiment, the compound is selected from the following:

-   -   3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(4-carboxymethoxy-3,5-dimethoxyphenyl)-2-propen-1-one        sodium salt;    -   3-[2,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(4-carboxyrnethoxy-3,5-dimethoxyphenyl)-2-propen-1-one;    -   3-[2,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(4-carboxymethoxy-3,5-dimethoxyphenyl)-2-propen-1-one        sodium salt;    -   3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(4-hydroxy-3,5-dimethoxyphenyl)-2-propen-1-one;    -   3-[2,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(4-hydroxy-3,5-dimethoxyphenyl)-2-propen-1-one;    -   3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(4-carboxymethoxy-3,5-dimethoxyphenyl)-2-propen-1-one;    -   3-[2,4-dimethoxy-5-(thien-2-yl)-phenyl]-1-(4-carboxymethoxy-3,5-dimethoxyphenyl)-2-propen-1-one;    -   3-[5-(benzo[b]thien-2-yl)-3,4-dimethoxyphenyl]-1-(2,3,4-trimethoxyphenyl)-2-propen-1-one;    -   3-[2-methoxy-5-(4-methylthien-2-yl)phenyl]-1-(3,4,5-trimethoxy        phenyl)-2-propen-1-one;    -   3-[2-methoxy-5-(5-methylthien-2-yl)phenyl]-1-(3,4-dimethoxyphenyl)-2-propen-1-one;    -   3-[2-methoxy-5-(5-methylthien-2-yl)phenyl]-1-(3,4,5-trimethoxy        phenyl)-2-propen-1-one;    -   3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(2,5-dimethoxyphenyl)-2-propen-1-one;    -   3-[3,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one;    -   3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3,4-dichloro-2-hydroxyphenyl)-2-propen-1-one        sodium salt;    -   3-[2-methoxy-5-(4-methylthien-2-yl)phenyl]-1-(3,4-dimethoxyphenyl)-2-propen-1-one;    -   3-[3,4-dimethoxy-5-(3-pyridyl)phenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one;    -   3-[2,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one;    -   3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3,5-dimethoxyphenyl)-2-propen-1-one;    -   3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(4-iodo-2-methoxyphenyl)-2-propen-1-one;    -   3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3-methoxy-4-(4-pyridylmethoxyphenyl)-2-propen-1-one,        hydrochloride salt;    -   3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3-methoxy-4-(2-pyridylmethoxyphenyl)-2-propen-1-one        hydrochloride salt;    -   3-(3,4-difluorophenyl)-1-[2-methoxy-4-(thien-2-yl)phenyl]-2-propen-1-one;    -   3-[5-(benzo[b]thien-2-yl)-2-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one;    -   3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3,4-dichloro-2-hydroxyphenyl)-2-propen-1-one;    -   3-[5-(benzo[b]thien-2-yl)-2-methoxyphenyl]-1-(3,4-dimethoxyphenyl)-2-propen-1-one;    -   3-[2,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(2,3,4-trimethoxyphenyl)-2-propen-1-one;    -   3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3-methoxy-4-(2-pyridylmethoxphenyl)-2-propen-1-one;    -   3-[2-methoxy-5-(5-methylthien-2-yl)phenyl]-1-(3,4-methylenedioxyphenyl)-2-propen-1-one;    -   3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(4-hydroxy-3,5-dimethoxyphenyl)-2-propen-1-one        sodium salt;    -   3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3-methoxy-4-(3-pyridylmethoxphenyl)-2-propen-1-one;    -   3-[5-(benzo[b]thien-2-yl)-2-methoxyphenyl]-1-(4-methoxyphenyl)-2-propen-1-one;    -   3-[3,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(2,3,4-trimethoxyphenyl)-2-propen-1-one;    -   3-[5-(5-acetylthien-2-yl)-3,4-dimethoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one;    -   3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(4-methoxyphenyl)-2-propen-1-one;    -   3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(2,6-dimethoxyphenyl)-2-propen-1-one;    -   3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3,4-dimethoxyphenyl)-2-propen-1-one;    -   3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(2,4,6-trimethoxyphenyl)-2-propen-1-one;    -   3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one;    -   3-[2-methoxy-5-(thien-2-yl)phenyl]-1-[4-(4-ethoxycarbonylenzyloxy)-3-methoxyphenyl]-2-propen-1-one;    -   3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-[4-(2,3-isopropylidenedioxy-1-propoxy)-3,5-dimethoxyphenyl]-2-propen-1-one;    -   3-[2-methoxy-5-(thien-2-yl)phenyl]-1-[3-methoxy-4-(4-pyridylmethoxy)phenyl]-2-propen-1-one;    -   3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3,4-methylenedioxyphenyl)-2-propen-1-one;    -   3-[2-methoxy-5-(4-methylthien-2-yl)phenyl]-1-(3,4-methylenedioxyphenyl)-2-propen-1-one;    -   3-(4-ethoxy-3-fluorophenyl)-1-[2-methoxy-5-(thien-2-yl)phenyl]-2-propen-1-one;    -   3-[5-(benzo[b]thien-2-yl)-2-carboxymethoxy-4-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one        sodium salt;    -   3-[5-(benzo[b]thien-2-yl)-4-carboxymethoxy-2-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one;    -   3-[5-(benzo[b]thien-2-yl)-4-carboxymethoxy-2-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one        sodium salt;    -   3-[2-carboxymethoxy-4-methoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one;    -   3-[2-carboxymethoxy-4-methoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one        sodium salt;    -   3-[4-carboxymethoxy-2-methoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one        sodium salt;    -   3-[4-carboxymethoxy-2-methoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one;    -   3-[5-(benzo        [b]thien-2-yl)-3,4-dimethoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one;    -   3-[5-(benzo        [b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one;    -   3-[5-(benzo        [b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-2-buten-1-one;    -   3-[2-methoxy-5-(thien-2-yl)phenyl]-1-[4-(4-carboxybenzyloxy)-3-methoxyphenyl]-2-propen-1-one;    -   3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3,4-difluorophenyl)-2-propen-1-one;    -   3-[4-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one;    -   3-[2-methoxy-5-(thien-2-yl)phenyl]-1-[4-(4-aminobenzyloxy)-3-methoxyphenyl]-2-propen-1-one;    -   3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(4-hydroxy-3-methoxyphenyl)-2-propen-1-one;    -   3-[5-(benzo        [b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(2,3,4-trimethoxyphenyl)-2-propen-1-one;    -   3-[5-(benzo        [b]thien-2-yl)-2-carboxymethoxy-4-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one;    -   3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-[3,5-dimethoxy-4-(2-morpholinoethoxy)phenyl]-2-propen-1-one;    -   3-[2-methoxy-5-(thien-2-yl)phenyl]-1-[-2-methoxy-4-(3-methoxyphenyl)phenyl]-2-propen-1-one;    -   3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(3,4-dimethoxyphenyl)-2-propen-1-one;    -   3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(2,5-dimethoxy-4-(thien-2-ylmethoxy)phenyl)-2-propen-1-one;    -   3-[4-(thien-2-yl)phenyl]-1-(3,4-dimethoxyphenyl)-2-propen-1-one;    -   3-[2-methoxy-4-(thien-2-yl)-phenyl]-1-[2-methoxy-4-(thien-2-yl)phenyl)-2-propen-1-one        phenyl]-2-propen-1-one;    -   2-[[3,4-dimethoxy-5-(thien-2-yl)phenyl]ethylene]-3,4-dihydro-6,7-dimethoxy-1(2H)-naphthalenone.        Stereoisomerism and Polymorphism

It is appreciated that compounds of the present invention having achiral center may exist in and be isolated in optically active andracemic forms. Some compounds may exhibit polymorphism. It is to beunderstood that the present invention encompasses any racemic,optically-active, diastereomeric, polymorphic, or stereoisomeric form,or mixtures thereof, of a compound of the invention, which possess theuseful properties described herein, it being well known in the art howto prepare optically active forms (for example, by resolution of theracemic form by recrystallization techniques, by synthesis fromoptically-active starting materials, by chiral synthesis, or bychromatographic separation using a chiral stationary phase).

Examples of methods to obtain optically active materials are known inthe art, and include at least the following.

-   -   i) physical separation of crystals—a technique whereby        macroscopic crystals of the individual enantiomers are manually        separated. This technique can be used if crystals of the        separate enantiomers exist, i.e., the material is a        conglomerate, and the crystals are visually distinct;    -   ii) simultaneous crystallization—a technique whereby the        individual enantiomers are separately crystallized from a        solution of the racemate, possible only if the latter is a        conglomerate in the solid state;    -   iii) enzymatic resolutions—a technique whereby partial or        complete separation of a racemate by virtue of differing rates        of reaction for the enantiomers with an enzyme;    -   iv) enzymatic asymmetric synthesis—a synthetic technique whereby        at least one step of the synthesis uses an enzymatic reaction to        obtain an enantiomerically pure or enriched synthetic precursor        of the desired enantiomer;    -   v) chemical asymmetric synthesis—a synthetic technique whereby        the desired enantiomer is synthesized from an achiral precursor        under conditions that produce asymmetry (i.e., chirality) in the        product, which may be achieved using chiral catalysts or chiral        auxiliaries;    -   vi) diastereomer separations—a technique whereby a racemic        compound is reacted with an enantiomerically pure reagent (the        chiral auxiliary) that converts the individual enantiomers to        diastereomers. The resulting diastereomers are then separated by        chromatography or crystallization by virtue of their now more        distinct structural differences and the chiral auxiliary later        removed to obtain the desired enantiomer;    -   vii) first- and second-order asymmetric transformations—a        technique whereby diastereomers from the racemate equilibrate to        yield a preponderance in solution of the diastereomer from the        desired enantiomer or where preferential crystallization of the        diastereomer from the desired enantiomer perturbs the        equilibrium such that eventually in principle all the material        is converted to the crystalline diastereomer from the desired        enantiomer. The desired enantiomer is then released from the        diastereomer;    -   viii) kinetic resolutions—this technique refers to the        achievement of partial or complete resolution of a racemate (or        of a further resolution of a partially resolved compound) by        virtue of unequal reaction rates of the enantiomers with a        chiral, non-racemic reagent or catalyst under kinetic        conditions;    -   ix) enantiospecific synthesis from non-racemic precursors—a        synthetic technique whereby the desired enantiomer is obtained        from non-chiral starting materials and where the stereochemical        integrity is not or is only minimally compromised over the        course of the synthesis;    -   x) chiral liquid chromatopraphy—a technique whereby the        enantiomers of a racemate are separated in a liquid mobile phase        by virtue of their differing interactions with a stationary        phase. The stationary phase can be made of chiral material or        the mobile phase can contain an additional chiral material to        provoke the differing interactions;    -   xi) chiral gas chromatography—a technique whereby the racemate        is volatilized and enantiomers are separated by virtue of their        differing interactions in the gaseous mobile phase with a column        containing a fixed non-racemic chiral adsorbent phase;    -   xii) extraction with chiral solvents—a technique whereby the        enantiomers are separated by virtue of preferential dissolution        of one enantiomer into a particular chiral solvent;    -   xiii) transport across chiral membranes—a technique whereby a        racemate is placed in contact with a thin membrane barrier. The        barrier typically separates two miscible fluids, one containing        the racemate, and a driving force such as concentration or        pressure differential causes preferential transport across the        membrane barrier. Separation occurs as a result of the        non-racemic chiral nature of the membrane which allows only one        enantiomer of the racemate to pass through.

II. Definitions

The term alkyl, as used herein, unless otherwise specified, refers to asaturated straight, branched, or cyclic, primary, secondary, or tertiaryhydrocarbon, including but not limited to those of C1 to C10, andpreferably C1-C4, including methyl, ethyl, propyl, isopropyl,cyclopropyl, methylcyclopropyl, butyl, isobutyl, t-butyl, sec-butyl,cyclobutyl, and (cyclopropyl)methyl. The alkyl group specificallyincludes fluorinated alkyls such as CF3 and other halogenated alkylssuch as CH2CF2, CF2CF3, the chloro analogs, and the like.

The alkyl group can be optionally substituted with one or more moietiesselected from the group consisting of aryl, heteroaryl, heterocyclic,carbocycle, alkoxy, heterocycloxy, heterocylalkoxy, aryloxy; arylalkoxy;heteroaryloxy; heteroarylalkoxy, carbohydrate, amino acid, amino acidesters, amino acid amides, alditol, halo, haloalkyl, hydroxyl, carboxyl,acyl, acyloxy, amino, amido, alkylamino, dialkylamino, arylamino, nitro,cyano, thiol, imide, sulfonic acid, sulfate, sulfonyl, sulfanyl,sulfinyl, sulfamoyl, carboxylic ester, carboxylic acid, amide,phosphonyl, phosphinyl, phosphoryl, thioester, thioether, oxime,hydrazine, carbamate, phosphonic acid, phosphate, phosphonate,phosphinate, sulfonamido, carboxamido, hydroxamic acid, sulfonylimide,substituted or unsubstituted urea connected through nitrogen includingbut not limited to NHCONH2 and NHCONHR; or any other desired functionalgroup that does not inhibit the pharmacological activity of thiscompound, either unprotected, or protected as necessary, as known tothose skilled in the art, for example, as taught in Greene, et al.,Protective Groups in Organic Synthesis, John Wiley and Sons, SecondEdition, 1991, hereby incorporated by reference.

The term aryl, as used herein, and unless otherwise specified, refers tophenyl, biphenyl, or naphthyl, and preferably phenyl. The aryl group canbe optionally substituted with one or more of the moieties selected fromthe group consisting of alkyl, heteroaryl, heterocyclic, carbocycle,alkoxy, aryloxy, aryloxy; arylalkoxy; heteroaryloxy; heteroarylalkoxy,carbohydrate, amino acid, amino acid esters, amino acid amides, alditol,halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido,alkylamino, dialkylamino, arylamino, nitro, cyano, thiol, imide,sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfamoyl,carboxylic ester, carboxylic acid, amide, phosphonyl, phosphinyl,phosphoryl, thioester, thioether, oxime, hydrazine, carbamate,phosphonic acid, phosphate, phosphonate, phosphinate, sulfonamido,carboxamido, hydroxamic acid, sulfonylimide or any other desiredfunctional group that does not inhibit the pharmacological activity ofthis compound, either unprotected, or protected as necessary, as knownto those skilled in the art, for example, as taught in Greene, et al.,“Protective Groups in Organic Synthesis,” John Wiley and Sons, SecondEdition, 1991. Alternatively, adjacent groups on the aryl ring maycombine to form a 5 to 7 membered carbocyclic, aryl, heteroaryl orheterocylic ring. In another embodiment, the aryl ring is substitutedwith an optionally substituted cycloalkyl (such as cyclopentyl orcylcohexyl), or an alkylene dioxy moiety (for example methylenedioxy).

The term heterocyclic refers to a nonaromatic cyclic group that may bepartially (contains at least one double bond) or fully saturated andwherein there is at least one heteroatom, such as oxygen, sulfur,nitrogen, or phosphorus in the ring. The term heteroaryl orheteroaromatic, as used herein, refers to an aromatic that includes atleast one sulfur, oxygen, nitrogen or phosphorus in the aromatic ring.Nonlimiting examples of heterocylics and heteroaromatics arepyrrolidinyl, tetrahydrofuryl, piperazinyl, piperidinyl, morpholino,thiomorpholino, tetrahydropyranyl, imidazolyl, pyrolinyl, pyrazolinyl,indolinyl, dioxolanyl, or 1,4-dioxanyl. aziridinyl, furyl, furanyl,pyridyl, pyrimidinyl, benzoxazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, 1,3,4-thiadiazole, indazolyl, 1,3,5-triazinyl,thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl,quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl,isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl,benzothiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl,quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl,pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-oxadiazole,thiazine, pyridazine, or pteridinyl wherein said heteroaryl orheterocyclic group can be optionally substituted with one or moresubstituent selected from the same substituents as set out above foraryl groups. Functional oxygen and nitrogen groups on the heteroarylgroup can be protected as necessary or desired. Suitable protectinggroups can include trimethylsilyl, dimethylhexylsilyl,t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl or substitutedtrityl, alkyl groups, acyl groups such as acetyl and propionyl,methanesulfonyl, and p-toluenelsulfonyl.

The term thienyl refers to a five member cyclic group wherein the ringcontains one sulfur atom and two double bonds. The thienyl group canoptionally be substituted with one or more moieties selected from thegroup consisting of those described above for aryl substituents.

The term benzothienyl refers to a five member cyclic group wherein thering contains one sulfur atom and two double bonds fused to a phenylring. The benzothienyl group can optionally be substituted with one ormore moieties selected from the group consisting of those describedabove for aryl substituents.

The term aralkyl, as used herein, and unless otherwise specified, refersto an aryl group as defined above linked to the molecule through analkyl group as defined above. The aryl and alkyl portions can beoptionally substituted as described above.

The term heteroaralkyl, as used herein, and unless otherwise specified,refers to an heteroaryl group as defined above linked to the moleculethrough an alkyl group as defined above.

The term heterocyclealkyl, as used herein, refers to a heterocyclicgroup bound to the molecule through an alkyl group. The heterocyclicgroup and the alkyl group can be optionally substituted as describedabove.

The term aryloxy, as used herein, refers to an aryl group bound to themolecule through an oxygen atom. The aryl group can be optionallysubstituted as set out above for aryl groups.

The term heteroaryloxy, as used herein, refers to a heteroaryl groupbound to the molecule through an oxygen atom. The heteroaryl group canbe optionally substituted as set out above for aryl groups.

The term aralkoxy refers to an aryl group attached to an alkyl groupwhich is attached to the molecule through an oxygen atom. The aryl andalkyl groups can be optionally substituted as described above.

The term heterocyclearalkoxy refers to a heterocyclic group attached toan aryl group attached to an alkyl-O— group. The heterocyclic, aryl andalkyl groups can be optionally substituted as described above.

The term halo or halogen, as used herein, includes chloro, bromo, iodoand fluoro.

The term alkoxy, as used herein, and unless otherwise specified, refersto a moiety of the structure —O-alkyl, wherein alkyl is as definedabove. The alkyl group can be optionally substituted as described above.Alkoxy groups can include OCF3, OCH2CF3, OCF2CF3 and the like.

The term alkylthio as used herein refers to an alkyl group attached tothe molecule through a sulfur atom. The alkyl group can be optionallysubstituted as described above.

The term acyl, as used herein, refers to a group of the formula C(O)R′,wherein R′ is an alkyl, aryl, alkaryl or aralkyl group, or substitutedalkyl, aryl, aralkyl or alkaryl, wherein these groups are as definedabove.

The term “alditol,” as referred to herein, and unless otherwisespecified, refers to a carbohydrate in which the aldehyde or ketonegroup has been reduced to an alcohol moiety. The alditols of the presentinvention can also be optionally substituted or deoxygenated at one ormore positions. Exemplary substituents include hydrogen, halo,haloalkyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives,alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano,sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl,ester, carboxylic acid, amide, amino acid, amino acid esters and amides,phosphonyl, phosphinyl, phosphoryl, thioester, thioether, oxime,hydrazine, carbamate, phosphonic acid, phosphonate, or any other viablefunctional group that does not inhibit the pharmacological activity ofthis compound. Particular exemplary substituents include amine and halo,particularly fluorine. The substituent or alditol can be eitherunprotected, or protected as necessary, as known to those skilled in theart, for example, as taught in Greene, et al., Protective Groups inOrganic Synthesis, John Wiley and Sons, Second Edition, 1991, herebyincorporated by reference.

The alditol may have 3, 4, 5, 6 or 7 carbons. Examples of usefulalditols are those derived from reduction of monosaccharides, includingspecifically those derived from the reduction of pyranose and furanosesugars.

The term “carbohydrate,” as referred to herein, and unless otherwisespecified, refers to a compound of carbon, hydrogen and oxygen thatcontains an aldehyde or ketone group in combination with at least twohydroxyl groups. The carbohydrates of the present invention can also beoptionally substituted or deoxygenated at one or more positions.Carbohydrates thus include substituted and unsubstitutedmonosaccharides, disaccharides, oligosaccharides, and polysaccharides.The saccharide can be an aldose or ketose, and may comprise 3, 4, 5, 6,or 7 carbons. In one embodiment the carbohydrates are monosaccharides.In another embodiment the carbohydrates are pyranose and furanosesugars.

Non limiting examples of pyranose and furanose sugars include threose,ribulose, ketose, gentiobiose, aldose, aldotetrose, aldopentose,aldohexose, ketohexose, ketotetrose, ketopentose, erythrose, threose,ribose, deoxyribose, arabinose, xylose, lyxose, allose, altrose,glucose, mannose, gulose, idose, glactose, talose, erythrulose,ribulose, xylulose, psicose, fructose, sorbose, tagatose, dextrose,maltose, lactose, sucrose, cellulose, aldose, amylose, palatinose,trehalose, turanose, cellobiose, amylopectin, glucosamine, mannosamine,fucose, phamnose, glucuronate, gluconate, glucono-lactone, muramic acid,abequose, rhamnose, gluconic acid, glucuronic acid, and galactosamine.

The carbohydrate can be optionally deoxygenated at any correspondingC-position, and/or substituted with one or more moieties such ashydrogen, halo, haloalkyl, carboxyl, acyl, acyloxy, amino, amido,carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy,aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl,sulfinyl, sulfamonyl, ester, carboxylic acid, amide, amino acid, aminoacid esters, amides, phosphonyl, phosphinyl, phosphoryl, thioester,thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, orany other viable functional group that does not inhibit thepharmacological activity of this compound. Particular exemplarysubstituents include amine and halo, particularly fluorine. Thesubstituent or carbohydrate can be either unprotected, or protected asnecessary, as known to those skilled in the art, for example, as taughtin Greene, et al., Protective Groups in Organic Synthesis, John Wileyand Sons, Second Edition, 1991, hereby incorporated by reference.

The term “protected” as used herein and unless otherwise defined refersto a group that is added to an oxygen, nitrogen, or phosphorus atom toprevent its further reaction or for other purposes. A wide variety ofoxygen and nitrogen protecting groups are known to those skilled in theart of organic synthesis. The term aryl, as used herein, and unlessotherwise specified, refers to phenyl, biphenyl, or naphthyl, andpreferably phenyl. The aryl group can be optionally substituted with oneor more moieties selected from the group consisting of hydroxyl, amino,alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid,sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected,or protected as necessary, as known to those skilled in the art, forexample, as taught in Greene, et al., Protective Groups in OrganicSynthesis, John Wiley and Sons, Second Edition, 1991.

As used herein, the term “patient” refers to warm-blooded animals ormammals, and in particular humans, who are in need of the therapydescribed herein. The term host, as used herein, refers to a unicellularor multicellular organism, including cell lines and animals, andpreferably a human.

III. Pharmaceutically Acceptable Salt Formulations

In cases where compounds are sufficiently basic or acidic to form stablenontoxic acid or base salts, administration of the compound as apharmaceutically acceptable salt may be appropriate. The term“pharmaceutically acceptable salts” or “complexes” refers to salts orcomplexes that retain the desired biological activity of the compoundsof the present invention and exhibit minimal undesired toxicologicaleffects.

Examples of pharmaceutically acceptable salts are organic acid additionsalts formed with acids, which form a physiological acceptable anion,for example, tosylate, methanesulfonate, acetate, citrate, malonate,tartarate, succinate, benzoate, ascorbate, α-ketoglutarate andα-glycerophosphate. Suitable inorganic salts may also be formed,including, sulfate, nitrate, bicarbonate and carbonate salts.Alternatively, the pharmaceutically acceptable salts may be made withsufficiently basic compounds such as an amine with a suitable acidaffording a physiologically acceptable anion. Alkali metal (for example,sodium, potassium or lithium) or alkaline earth metal (for examplecalcium) salts of carboxylic acids can also be made.

Nonlimiting examples of such salts are (a) acid addition salts formedwith inorganic acids (for example, hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, nitric acid, and the like), and saltsformed with organic acids such as acetic acid, oxalic acid, tartaricacid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannicacid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonicacid, naphthalenedisulfonic acid, and polygalcturonic acid; (b) baseaddition salts formed with metal cations such as zinc, calcium, bismuth,barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium,potassium, and the like, or with a cation formed from ammonia,N,N-dibenzylethylenediamine, D-glucosamine, tetraethylammonium, orethylenediamine; or (c) combinations of (a) and (b); e.g., a zinctannate salt or the like. Also included in this definition arepharmaceutically acceptable quaternary salts known by those skilled inthe art, which specifically include the quaternary ammonium salt of theformula —NR+A—, wherein R is as defined above and A is a counterion,including chloride, bromide, iodide, —O-alkyl, toluenesulfonate,methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate,succinate, acetate, glycolate, maleate, malate, citrate, tartrate,ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, anddiphenylacetate).

Pharmaceutically acceptable prodrugs refer to a compound that ismetabolized, for example hydrolyzed or oxidized, in the host to form thecompound of the present invention. Typical examples of prodrugs includecompounds that have biologically labile protecting groups on afunctional moiety of the active compound. Prodrugs include compoundsthat can be oxidized, reduced, aminated, deaminated, hydroxylated,dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated,acylated, deacylated, phosphorylated, dephosphorylated to produce theactive compound. The compounds of this invention possessanti-inflammatory activity, or are metabolized to a compound thatexhibits such activity.

Any of the compounds described herein can be administered as a prodrugto increase the activity, bioavailability, stability or otherwise alterthe properties of the compound. A number of prodrug ligands are known.In general, alkylation, acylation or other lipophilic modification ofthe compound will increase the stability of the chalcone. Examples ofsubstituent groups that can replace one or more hydrogens on thecompound are alkyl, aryl, steroids, carbohydrates, including sugars,1,2-diacylglycerol and alcohols. Many are described in R. Jones and N.Bischofberger, Antiviral Research, 27 (1995) 1-17. Any of these can beused in combination with the disclosed compounds to achieve a desiredeffect.

IV. Inflammatory Diseases

The compounds of the present invention can be used to treat any disorderthat is mediated by VCAM. VCAM is upregulated in a wide variety ofdisease states, including but not limited to arthritis, asthma,dermatitis, psoriasis, cystic fibrosis, post transplantation late andchronic solid organ rejection, multiple sclerosis, systemic lupuserythematosis, inflammatory bowel diseases, autoimmune diabetes,diabetic retinopathy, rhinitis, ischemia-reperfusion injury,post-angioplasty restenosis, chronic obstructive pulmonary disease(COPD), glomerulonephritis, Graves disease, gastrointestinal allergies,and conjunctivitis.

Nontlimiting examples of arthritis include rheumatoid (such assoft-tissue rheumatism and non-articular rheumatism, fibromyalgia,fibrositis, muscular rheumatism, myofascil pain, humeral epicondylitis,frozen shoulder, Tietze's syndrome, fascitis, Dendonitis, tenosynovitis,bursitis), juvenile chronic, spondyloarthropaties (ankylosingspondylitis), osteoarthritis, hyperuricemia and arthritis associatedwith acute gout, chronic gout and systemic lupus erythematosus.

Human endothelial disorders mediated by VCAM-1 include psoriasis,eczematous dermatitis, Kaposi's sarcoma, as well as proliferativedisorders of smooth muscle cells.

In yet another embodiment, the compounds disclosed herein can beselected to treat anti-inflammatory conditions that are mediated bymononuclear leucocytes.

In one embodiment, the compounds of the present invention are selectedfor the prevention or treatment of tissue or organ transplant rejection.Treatment and prevention of organ or tissue transplant rejectionincludes, but are not limited to treatment of recipients of heart, lung,combined heart-lung, liver, kidney, pancreatic, skin, spleen, smallbowel, or corneal transplants. The compounds can also be used in theprevention or treatment of graft-versus-host disease, such as sometimesoccurs following bone marrow transplantation.

In an alternative embodiment, the compounds described herein are usefulin both the primary and adjunctive medical treatment of cardiovasculardisease. The compounds are used in primary treatment of, for example,coronary disease states including atherosclerosis, post-angioplastyrestenosis, coronary artery diseases and angina. The compounds can beadministered to treat small vessel disease that is not treatable bysurgery or angioplasty, or other vessel disease in which surgery is notan option. The compounds can also be used to stabilize patients prior torevascularization therapy.

In addition to inhibiting the expression of VCAM-1, the disubstituted1,3-bis-(substituted-phenyl)-2-propen-1-ones have the additionalproperties of inhibiting monocyte chemoattractant protein-1 (MCP-1) andsmooth muscle proliferation. MCP-1 is a chemoattractant protein producedby endothelial cells, smooth muscle cells as well as macrophages. MCP-1promotes integrin activation on endothelial cells thereby facilitatingadhesion of leukocytes to VCAM-1, and MCP-1 is a chemoattractant formonocytes. MCP-1 has been shown to play a role in leukocyte recruitmentin a number of chronic inflammatory diseases including atherosclerosis,rheumatoid arthritis, and asthma. Its expression is upregulated in thesediseases and as such inhibition of MCP-1 expression represents adesirable property of anti-inflammatory therapeutics. Furthermore,smooth muscle cell hyperplasia and resulting tissue remodeling anddecreased organ function is yet another characteristic of many chronicinflammatory diseases including atherosclerosis, chronic transplantrejection and asthma. Inhibition of the hyperproliferation of smoothmuscle cells is another desirable property for therapeutic compounds.

V. Combination and Alternation Therapy

Any of the compounds disclosed herein can be administered in combinationor alternation with a second biologically active agent to increase itseffectiveness against the target disorder.

In combination therapy, effective dosages of two or more agents areadministered together, whereas during alternation therapy an effectivedosage of each agent is administered serially. The dosages will dependon absorption, inactivation and excretion rates of the drug as well asother factors known to those of skill in the art. It is to be noted thatdosage values will also vary with the severity of the condition to bealleviated. It is to be further understood that for any particularsubject, specific dosage regimens and schedules should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions.

The efficacy of a drug can be prolonged, augmented, or restored byadministering the compound in combination or alternation with a second,and perhaps third, agent that induces a different biological pathwayfrom that caused by the principle drug. Alternatively, thepharmacokinetics, biodistribution or other parameter of the drug can bealtered by such combination or alternation therapy. In general,combination therapy is typically preferred over alternation therapybecause it induces multiple simultaneous stresses on the condition.

Any method of alternation can be used that provides treatment to thepatient. Nonlimiting examples of alternation patterns include 1-6 weeksof administration of an effective amount of one agent followed by 1-6weeks of administration of an effective amount of a second agent. Thealternation schedule can include periods of no treatment. Combinationtherapy generally includes the simultaneous administration of aneffective ratio of dosages of two or more active agents.

Illustrative examples of specific agents that can be used in combinationor alternation with the chalcones of the present invention are describedbelow in regard to asthma and arthritis. The agents set out below orothers can alternatively be used to treat a host suffering from any ofthe other disorders listed in Section IV or that are mediated by VCAM orMCP-1. Illustrative second biologically active agents for the treatmentof cardiovascular disease are also provided below.

Asthma

In one embodiment, the compound of the present invention is administeredin combination or alternation with heparin, frusemide, ranitidine, anagent that effects respiratory function, such as DNAase, orimmunosuppressive agents, IV gamma globulin, troleandomycin, cyclosporin(Neoral), methotrexate, FK-506, gold compounds such as Myochrysine (goldsodium thiomalate), platelet activating factor (PAF) antagonists such asthromboxane inhibitors, leukotriene-D4-receptor antagonists such asAccolate (zafirlukast), Ziflo (zileuton), leukotriene C1 or C2antagonists and inhibitors of leukotriene synthesis such as zileuton forthe treatment of asthma, or an inducible nitric oxide synthaseinhibitor.

In another embodiment, the active compound is administered incombination or alternation with one or more other prophylactic agent(s).Examples of prophylactic agents that can be used in alternation orcombination therapy include but are not limited to sodium cromoglycate,Intal (cromolyn sodium, Nasalcrom, Opticrom, Crolom, Ophthalmic Crolom),Tilade (nedocromil, nedocromil sodium) and ketotifen.

In another embodiment, the active compound is administered incombination or alternation with one or more other β2-adrenergicagonist(s) (β agonists). Examples of β-adrenergic agonists (β agonists)that can be used in alternation or combination therapy include but arenot limited to albuterol (salbutamol, Proventil, Ventolin), terbutaline,Maxair (pirbuterol), Serevent (salmeterol), epinephrine, metaproterenol(Alupent, Metaprel), Brethine (Bricanyl, Brethaire, terbutalinesulfate), Tornalate (bitolterol), isoprenaline, ipratropium bromide,bambuterol hydrochloride, bitolterol meslyate, broxaterol, carbuterolhydrochloride, clenbuterol hydrochloride, clorprenaline hydrochloride,efirmoterol fumarate, ephedra (source of alkaloids), ephedrine(ephedrine hydrochloride, ephedrine sulfate), etafedrine hydrochloride,ethylnoradrenaline hydrochloride, fenoterol hydrochloride, hexoprenalinehydrochloride, isoetharine hydrochloride, isoprenaline, mabuterol,methoxyphenamine hydrochloride, methylephedrine hydrochloride,orciprenaline sulphate, phenylephrine acid tartrate, phenylpropanolamine(phenylpropanolamine polistirex, phenylpropanolamine sulphate),pirbuterol acetate, procaterol hydrochloride, protokylol hydrochloride,psuedoephedrine (psuedoephedrine polixtirex, psuedoephedrine tannate,psuedoephedrine hydrochloride, psuedoephedrine sulphate), reproterolhydrochloride, rimiterol hydrobromide, ritodrine hydrochloride,salmeterol xinafoate, terbutaline sulphate, tretoquinol hydrate andtulobuterol hydrochloride.

In another embodiment, the active compound is administered incombination or alternation with one or more other corticosteriod(s).Examples of corticosteriods that can be used in alternation orcombination therapy include but are not limited to glucocorticoids (GC),Aerobid (Aerobid-M, flunisolide), Azmacort (triamcinolone acetonide),Beclovet (Vanceril, beclomethasone dipropionate), Flovent (fluticasone),Pulmicort (budesonide), prednisolone, hydrocortisone, adrenaline,Alclometasone Dipropionate, Aldosterone, Amcinonide, BeclomethasoneDipropionate, Bendacort, Betamethasone (Betamethasone Acetate,Betamethasone Benzoate, Betamethasone Dipropionate, Betamethasone SodiumPhosphate, Betamethasone Valerate), Budesonide, Ciclomethasone,Ciprocinonide, Clobetasol Propionate, Clobetasone Butyrate, ClocortolonePivalate, Cloprednol, Cortisone Acetate, Cortivazol, Deflazacort,Deoxycortone Acetate (Deoxycortone Pivalate), Deprodone, Desonide,Desoxymethasone, Dexamethasone (Dexamethasone Acetate, DexamethasoneIsonicotinate, Dexamethasone Phosphate, Dexamethasone SodiumMetasulphobenzoate, Dexamethasone Sodium Phosphate), DichlorisoneAcetate, Diflorasone Diacetate, Diflucortolone Valerate, Difluprednate,Domoprednate, Endrysone, Fluazacort, Fluclorolone Acetonide,Fludrocortisone Acetate, Flumethasone (Flumethasone Pivalate),Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluocortin Butyl,Fluocortolone (Fluocortolone Hexanoate, Fluocortolone Pivalate),Fluorometholone (Fluorometholone Acetate), Fluprednidene Acetate,Fluprednisolone, Flurandrenolone, Fluticasone Propionate, Formocortal,Halcinonide, Halobetasol Propionate, Halometasone, HydrocortamateHydrochloride, Hydrocortisone (Hydrocortisone Acetate, HydrocortisoneButyrate, Hydrocortisone Cypionate, Hydrocortisone Hemisuccinate,Hydrocortisone Sodium Phosphate, Hydrocortisone Sodium Succinate,Hydrocortisone Valerate), Medrysone, Meprednisone, Methylprednisolone(Methylprednisolone Acetate, Methylprednisolone ,Hemisuccinate,Methylprednisolone Sodium Succinate), Mometasone Furoate, ParamethasoneAcetate, Prednicarbate, Prednisolamate Hydrochloride, Prednisolone(Prednisolone Acetate, Prednisolone Hemisuccinate, PrednisoloneHexanoate, Prednisolone Pivalate, Prednisolone SodiumMetasulphobenzoate, Prednisolone Sodium Phosphate, Prednisolone SodiumSuccinate, Prednisolone Steaglate, Prednisolone Tebutate), Prednisone(Prednisone Acetate), Prednylidene, Procinonide, Rimexolone, SuprarenalCortex, Tixocortol Pivalate, Triamcinolone (Triamcinolone Acetonide,Triamcinolone Diacetate and Triamcinolone Hexacetonide).

In another embodiment, the active compound is administered incombination or alternation with one or more other antihistimine(s) (H1receptor antagonists). Examples of antihistimines (H1 receptorantagonists) that can be used in alternation or combination therapyinclude alkylamines, ethanolamines ethylenediamines, piperazines,piperidines or phenothiazines. Some non-limiting examples ofantihistimes are Chlortrimeton (Teldrin, chlorpheniramine), Atrohist(brompheniramine, Bromarest, Bromfed, Dimetane), Actidil (triprolidine),Dexchlor (Poladex, Polaramine, dexchlorpheniramine), Benadryl(diphen-hydramine), Tavist (clemastine), Dimetabs (dimenhydrinate,Dramamine, Marmine), PBZ (tripelennamine), pyrilamine, Marezine(cyclizine), Zyrtec (cetirizine), hydroxyzine, Antivert (meclizine,Bonine), Allegra (fexofenadine), Hismanal (astemizole), Claritin(loratadine), Seldane (terfenadine), Periactin (cyproheptadine),Nolamine (phenindamine, Nolahist), Phenameth (promethazine, Phenergan),Tacaryl (methdilazine) and Temaril (trimeprazine).

Alternatively, the compound of the present invention is administered incombination or alternation with

-   -   (a) xanthines and methylxanthines, such as Theo-24        (theophylline, Slo-Phylline, Uniphyllin, Slobid, Theo-Dur),        Choledyl (oxitriphylline), aminophylline;    -   (b) anticholinergic agents (antimuscarinic agents) such as        belladonna alkaloids, Atrovent (ipratropium bromide), atropine,        oxitropium bromide;    -   (c) phosphodiesterase inhibitors such as zardaverine;    -   (d) calcium antagonists such as nifedipine; or    -   (e) potassium activators such as cromakalim for the treatment of        asthma.        Arthritic Disorders

In one embodiment, the compound of the present invention can also beadministered in combination or alternation with apazone, amitriptyline,chymopapain, collegenase, cyclobenzaprine, diazepam, fluoxetine,pyridoxine, ademetionine, diacerein, glucosamine, hylan (hyaluronate),misoprostol, paracetamol, superoxide dismutase mimics, TNFα receptorantagonists, TNFα antibodies, P38 Kinase inhibitors, tricyclicantidepressents, cJun kinase inhibitors or immunosuppressive agents, IVgamma globulin, troleandomycin, cyclosporin (Neoral), methotrexate,FK-506, gold compounds such as Myochrysine (gold sodium thiomalate),platelet activating factor (PAF) antagonists such as thromboxaneinhibitors, leukotriene-D4-receptor antagonists such as Accolate(zafirlukast), Ziflo (zileuton), leukotriene C1, C2 antagonists andinhibitors of leukotriene synthesis such as zileuton for the treatmentof arthritic disorders, inducible nitric oxide sythase inhibitors.

In another embodiment, the active compound is administered incombination or alternation with one or more other corticosteriod(s).Examples of corticosteriods that can be used in alternation orcombination therapy include but are not limited to glucocorticoids (GC),Aerobid (Aerobid-M, flunisolide), Azmacort (triamcinolone acetonide),Beclovet (Vanceril, beclomethasone dipropionate), Flovent (fluticasone),Pulmicort (budesonide), prednisolone, hydrocortisone, adrenaline,Alclometasone Dipropionate, Aldosterone, Amcinonide, BeclomethasoneDipropionate, Bendacort, Betamethasone (Betamethasone Acetate,Betamethasone Benzoate, Betamethasone Dipropionate, Betamethasone SodiumPhosphate, Betamethasone Valerate), Budesonide, Ciclomethasone,Ciprocinonide, Clobetasol Propionate, Clobetasone Butyrate, ClocortolonePivalate, Cloprednol, Cortisone Acetate, Cortivazol, Deflazacort,Deoxycortone Acetate (Deoxycortone Pivalate), Deprodone, Desonide,Desoxymethasone, Dexamethasone (Dexamethasone Acetate, DexamethasoneIsonicotinate, Dexamethasone Phosphate, Dexamethasone SodiumMetasulphobenzoate, Dexamethasone Sodium Phosphate), DichlorisoneAcetate, Diflorasone Diacetate, Diflucortolone Valerate, Difluprednate,Domoprednate, Endrysone, Fluazacort, Fluclorolone Acetonide,Fludrocortisone Acetate, Flumethasone (Flumethasone Pivalate),Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluocortin Butyl,Fluocortolone (Fluocortolone Hexanoate, Fluocortolone Pivalate),Fluorometholone (Fluorometholone Acetate), Fluprednidene Acetate,Fluprednisolone, Flurandrenolone, Fluticasone Propionate, Formocortal,Halcinonide, Halobetasol Propionate, Halometasone, HydrocortamateHydrochloride, Hydrocortisone (Hydrocortisone Acetate, HydrocortisoneButyrate, Hydrocortisone Cypionate, Hydrocortisone Hemisuccinate,Hydrocortisone Sodium Phosphate, Hydrocortisone Sodium Succinate,Hydrocortisone Valerate), Medrysone, Meprednisone, Methylprednisolone(Methylprednisolone Acetate, Methylprednisolone ,Hemisuccinate,Methylprednisolone Sodium Succinate), Mometasone Furoate, ParamethasoneAcetate, Prednicarbate, Prednisolamate Hydrochloride, Prednisolone(Prednisolone Acetate, Prednisolone Hemisuccinate, PrednisoloneHexanoate, Prednisolone Pivalate, Prednisolone SodiumMetasulphobenzoate, Prednisolone Sodium Phosphate, Prednisolone SodiumSuccinate, Prednisolone Steaglate, Prednisolone Tebutate), Prednisone(Prednisone Acetate), Prednylidene, Procinonide, Rimexolone, SuprarenalCortex, Tixocortol Pivalate, Triamcinolone (Triamcinolone Acetonide,Triamcinolone Diacetate and Triamcinolone Hexacetonide).

In another embodiment, the active compound is administered incombination or alternation with one or more other non-steroidalanti-inflammatory drug(s) (NSAIDS). Examples of NSAIDS that can be usedin alternation or combination therapy are carboxylic acids, propionicacids, fenamates, acetic acids, pyrazolones, oxicans, alkanones, goldcompounds and others that inhibit prostaglandin synthesis, preferably byselectively inhibiting cylcooxygenase-2 (COX-2). Some nonlimitingexamples of COX-2 inhibitors are Celebrex (celecoxib) and Vioxx(rofacoxib). Some non-limiting examples of NSAIDS are aspirin(acetylsalicylic acid), Dolobid (diflunisal), Disalcid (salsalate,salicylsalicylate), Trisilate (choline magnesium trisalicylate), sodiumsalicylate, Cuprimine (penicillamine), Tolectin (tolmetin), ibuprofen(Motrin, Advil, Nuprin Rufen), Naprosyn (naproxen, Anaprox, naproxensodium), Nalfon (fenoprofen), Orudis (ketoprofen), Ansaid(flurbiprofen), Daypro (oxaprozin), meclofenamate (meclofanamic acid,Meclomen), mefenamic acid, Indocin (indomethacin), Clinoril (sulindac),tolmetin, Voltaren (diclofenac), Lodine (etodolac), ketorolac,Butazolidin (phenylbutazone), Tandearil (oxyphenbutazone), piroxicam(Feldene), Relafen (nabumetone), Myochrysine (gold sodium thiomalate),Ridaura (auranofin), Solganal (aurothioglucose), acetaminophen,colchicine, Zyloprim (allopurinol), Benemid (probenecid), Anturane(sufinpyrizone), Plaquenil (hydroxychloroquine), Aceclofenac,Acemetacin, Acetanilide, Actarit, Alclofenac, Alminoprofen, Aloxiprin,Aluminium Aspirin, Amfenac Sodium, Amidopyrine, Aminopropylone, AmmoniumSalicylate, Ampiroxicam, Amyl Salicylate, Anirolac, Aspirin, Auranofin,Aurothioglucose, Aurotioprol, Azapropazone, Bendazac (Bendazac Lysine),Benorylate, Benoxaprofen, Benzpiperylone, Benzydamine, Hydrochloride,Bomyl Salicylate, Bromfenac Sodium, Bufexamac, Bumadizone Calcium,Butibufen Sodium, Capsaicin, Carbaspirin Calcium, Carprofen,Chlorthenoxazin, Choline Magnesium Trisalicylate, Choline Salicylate,Cinmetacin, Clofexamide, Clofezone, Clometacin, Clonixin, Cloracetadol,Cymene, Diacerein, Diclofenac (Diclofenac Diethylammonium Salt,Diclofenac Potassium, Diclofenac Sodium), Diethylamine Salicylate,Diethylsalicylamide, Difenpiramide, Diflunisal, Dipyrone, Droxicam,Epirizole, Etenzamide, Etersalate, Ethyl Salicylate, Etodolac,Etofenamate, Felbinac, Fenbufen, Fenclofenac, Fenoprofen Calcium,Fentiazac, Fepradinol, Feprazone, Floctafenine, Flufenamic,Flunoxaprofen, Flurbiprofen (Flurbiprofen Sodium), Fosfosal, Furprofen,Glafenine, Glucametacin, Glycol Salicylate, Gold Keratinate,Harpagophytum Procumbens, Ibufenac, Ibuprofen, Ibuproxam, ImidazoleSalicylate, Indomethacin (Indomethacin Sodium), Indoprofen, Isamifazone,Isonixin, Isoxicam, Kebuzone, Ketoprofen, Ketorolac Trometamol, LithiumSalicylate, Lonazolac Calcium, Lomoxicam, Loxoprofen Sodium, LysineAspirin, Magnesium Salicylate, Meclofenamae Sodium, Mefenamic Acid,Meloxicam, Methyl Butetisalicylate, Methyl Gentisate, Methyl Salicylate,Metiazinic Acid, Metifenazone, Mofebutazone, Mofezolac, MorazoneHydrochloride, Momiflurnate, Morpholine Salicylate, Nabumetone, Naproxen(Naproxen Sodium), Nifenazone, Niflumic Acid, Nimesulide, Oxametacin,Oxaprozin, Oxindanac, Oxyphenbutazone, Parsalmide, Phenybutazone,Phenyramidol Hydrochloride, Picenadol Hydrochloride, PicolamineSalicylate, Piketoprofen, Pirazolac, Piroxicam, Pirprofen, Pranoprofen,Pranosal, Proglumetacin Maleate, Proquazone, Protizinic Acid,Ramifenazone, Salacetamide, Salamidacetic Acid, Salicylamide, Salix,Salol, Salsalate, Sodium Aurothiomalate, Sodium Gentisate, SodiumSalicylate, Sodium Thiosalicylate, Sulindac, Superoxide Dismutase(Orgotein, Pegorgotein, Sudismase), Suprofen, Suxibuzone, TenidapSodium, Tenoxicam, Tetrydamine, Thurfyl Salicylate, Tiaprofenic,Tiaramide Hydrochloride, Tinoridine Hydrochloride, Tolfenamic Acid,Tometin Sodium, Triethanolamine Salicylate, Ufenamate, Zaltoprofen,Zidometacin and Zomepirac Sodium.

Cardiovascular Disease

Compounds useful for combining with the compounds of the presentinvention for the treatment of cardiovascular disease encompass a widerange of therapeutic compounds.

Ileal bile acid transporter (IBAT) inhibitors, for example, are usefulin the present invention, and are disclosed in patent application no.PCT/US95/10863, herein incorporated by reference. More IBAT inhibitorsare described in PCT/US97/04076, herein incorporated by reference. Stillfurther IBAT inhibitors useful in the present invention are described inU.S. application Ser. No. 08/816,065, herein incorporated by reference.More IBAT inhibitor compounds useful in the present invention aredescribed in WO 98/40375, and WO 00/38725, herein incorporated byreference. Additional IBAT inhibitor compounds useful in the presentinvention are described in U.S. application Ser. No. 08/816,065, hereinincorporated by reference.

In another aspect, the second biologically active agent is a statin.Statins lower cholesterol by inhibiting of 3-hydroxy-3-methylglutarylcoenzyme A (HMG CoA) reductase, a key enzyme in the cholesterolbiosynthetic pathway. The statins decrease liver cholesterolbiosynthesis, which increases the production of LDL receptors therebydecreasing plasma total and LDL cholesterol (Grundy, S. M. New Engl. J.Med. 319, 24 (1988); Endo, A. J. Lipid Res. 33, 1569 (1992)). Dependingon the agent and the dose used, statins may decrease plasma triglyceridelevels and may increase HDLc. Currently the statins on the market arelovastatin (Merck), simvastatin (Merck), pravastatin (Sankyo and Squibb)and fluvastatin (Sandoz). A fifth statin, atorvastatin(Parke-Davis/Pfizer), is the most recent entrant into the statin market.Any of these statins or thers can be used in combination with thechalcones of the present invention.

MTP inhibitor compounds useful in the combinations and methods of thepresent invention comprise a wide variety of structures andfunctionalities. Some of the MTP inhibitor compounds of particularinterest for use in the present invention are disclosed in WO 00/38725,the disclosure from which is incorporated by reference. Descriptions ofthese therapeutic compounds can be found in Science, 282, 23 October1998, pp. 751-754, herein incorporated by reference.

Cholesterol absorption antagonist compounds useful in the combinationsand methods of the present invention comprise a wide variety ofstructures and functionalities. Some of the cholesterol absorptionantagonist compounds of particular interest for use in the presentinvention are described in U.S. Pat. No. 5,767,115, herein incorporatedby reference. Further cholesterol absorption antagonist compounds ofparticular interest for use in the present invention, and methods formaking such cholesterol absorption antagonist compounds are described inU.S. Pat. No. 5,631,365, herein incorporated by reference.

A number of phytosterols suitable for the combination therapies of thepresent invention are described by Ling and Jones in “DietaryPhytosterols: A Review of Metabolism, Benefits and Side Effects,” LifeSciences, 57 (3), 195-206 (1995). Without limitation, some phytosterolsof particular use in the combination of the present invention areClofibrate, Fenofibrate, Ciprofibrate, Bezafibrate, Gemfibrozil. Thestructures of the foregoing compounds can be found in WO 00/38725.

Phytosterols are also referred to generally by Nes (Physiology andBiochemistry of Sterols, American Oil Chemists' Society, Champaign,Ill., 1991, Table 7-2). Especially preferred among the phytosterols foruse in the combinations of the present invention are saturatedphytosterols or stanols. Additional stanols are also described by Nes(Id.) and are useful in the combination of the present invention. In thecombination of the present invention, the phytosterol preferablycomprises a stanol. In one preferred embodiment the stanol iscampestanol. In another preferred embodiment the stanol is cholestanol.In another preferred embodiment the stanol is clionastanol. In anotherpreferred embodiment the stanol is coprostanol. In another preferredembodiment the stanol is 22,23-dihydrobrassicastanol. In anotherembodiment the stanol is epicholestanol. In another preferred embodimentthe stanol is fucostanol. In another preferred embodiment the stanol isstigmastanol.

Another embodiment the present invention encompasses a therapeuticcombination of a compound of the present invention and an HDLc elevatingagent. In one aspect, the second HDLc elevating agent can be a CETPinhibitor. Individual CETP inhibitor compounds useful in the presentinvention are separately described in WO 00/38725, the disclosure ofwhich is herein incorporated by reference. Other individual CETPinhibitor compounds useful in the present invention are separatelydescribed in WO 99/14174, EP818448, WO 99/15504, WO 99/14215, WO98/04528, and WO 00/17166, the disclosures of which are hereinincorporated by reference. Other individual CETP inhibitor compoundsuseful in the present invention are separately described in WO 00/18724,WO 00/18723, and WO 00/18721, the disclosures of which are hereinincorporated by reference. Other individual CETP inhibitor compoundsuseful in the present invention are separately described in WO 98/35937,the disclosure of which is herein incorporated by reference.

In another aspect, the second biologically active agent can be a fibricacid derivative. Fibric acid derivatives useful in the combinations andmethods of the present invention comprise a wide variety of structuresand functionalities which have been reported and published in the art.

In another embodiment the present invention encompasses a therapeuticcombination of a compound of the present invention and anantihypertensive agent. Hypertension is defined as persistently highblood pressure. In another embodiment, the chalcone is administered incombination with an ACE inhibitor, a beta andrenergic blocker, alphaandrenergic blocker, angiotensin II receptor antagonist, vasodilator anddiuretic.

VI. Pharmaceutical Compositions

Any host organism, including a pateint, mammal, and specifically ahuman, suffering from any of the above-described conditions can betreated by the administration of a composition comprising an effectiveamount of the compound of formula (I) or a pharmaceutically acceptablesalt thereof, optionally in a pharmaceutically acceptable carrier ordiluent.

The composition can be administered in any desired manner, includingoral, topical, parenteral, intravenous, intradermal, intra-articular,intra-synovial, intrathecal, intra-arterial, intracardiac,intramuscular, subcutaneous, intraorbital, intracapsular, intraspinal,intrasternal, topical, transdermal patch, via rectal, vaginal orurethral suppository, peritoneal, percutaneous, nasal spray, surgicalimplant, internal surgical paint, infusion pump, or via catheter. In oneembodiment, the agent and carrier are administered in a slow releaseformulation such as an implant, bolus, microparticle, microsphere,nanoparticle or nanosphere. For standard information on pharmaceuticalformulations, see Ansel, et al., Pharmaceutical Dosage Forms and DrugDelivery Systems, Sixth Edition, Williams & Wilkins (1995).

An effective dose for any of the herein described conditions can bereadily determined by the use of conventional techniques and byobserving results obtained under analogous circumstances. In determiningthe effective dose, a number of factors are considered including, butnot limited to: the species of patient; its size, age, and generalhealth; the specific disease involved; the degree of involvement or theseverity of the disease; the response of the individual patient; theparticular compound administered; the mode of administration; thebioavailability characteristics of the preparation administered; thedose regimen selected; and the use of concomitant medication. Typicalsystemic dosages for all of the herein described conditions are thoseranging from 0.1 mg/kg to 500 mg/kg of body weight per day as a singledaily dose or divided daily doses. Preferred dosages for the describedconditions range from 5-1500 mg per day. A more particularly preferreddosage for the desired conditions ranges from 25-750 mg per day. Typicaldosages for topical application are those ranging from 0.001 to 100% byweight of the active compound.

The compound is administered for a sufficient time period to alleviatethe undesired symptoms and the clinical signs associated with thecondition being treated.

The active compound is included in the pharmaceutically acceptablecarrier or diluent in an amount sufficient to deliver to a patient atherapeutic amount of compound in vivo in the absence of serious toxiceffects.

The concentration of active compound in the drug composition will dependon absorption, inactivation, and excretion rates of the drug as well asother factors known to those of skill in the art. It is to be noted thatdosage values will also vary with the severity of the condition to bealleviated. It is to be further understood that for any particularsubject, specific dosage regimens should be adjusted over time accordingto the individual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat the dosage ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed composition. Theactive ingredient may be administered at once, or may be divided into anumber of smaller doses to be administered at varying intervals of time.

A preferred mode of administration of the active compound for systemicdelivery is oral. Oral compositions will generally include an inertdiluent or an edible carrier. They may be enclosed in gelatin capsulesor compressed into tablets. For the purpose of oral therapeuticadministration, the active compound can be incorporated with excipientsand used in the form of tablets, troches or capsules. Pharmaceuticallycompatible binding agents, and/or adjuvant materials can be included aspart of the composition.

The tablets, pills, capsules, troches and the like can contain any ofthe following ingredients, or compounds of a similar nature: a bindersuch as microcrystalline cellulose, gum tragacanth or gelatin; anexcipient such as starch or lactose, a disintegrating agent such asalginic acid, Primogel, or corn starch; a lubricant such as magnesiumstearate or Sterotes; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials whichmodify the physical form of the dosage unit, for example, coatings ofsugar, shellac, or other enteric agents.

The compound or its salts can be administered as a component of anelixir, suspension, syrup, wafer, chewing gum or the like. A syrup maycontain, in addition to the active compounds, sucrose as a sweeteningagent and certain preservatives, dyes and colorings and flavors.

The compound can also be mixed with other active materials that do notimpair the desired action, or with materials that supplement the desiredaction. The compounds can also be administered in combination withnonsteroidal antiinflammatories such as ibuprofen, indomethacin,fenoprofen, mefenamic acid, flufenamic acid, sulindac. The compound canalso be administered with corticosteriods.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include the following components: a sterilediluent such as water for injection, saline solution, fixed oils,polyethylene glycols, glycerine, propylene glycol or other syntheticsolvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. pH can be adjusted withacids or bases, such as hydrochloric acid or sodium hydroxide. Theparenteral preparation can be enclosed in ampoules, disposable syringesor multiple dose vials made of glass or plastic.

If administered intravenously, preferred carriers are physiologicalsaline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) orphosphate buffered saline (PBS).

In a preferred embodiment, the active compounds are prepared withcarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) are also preferred as pharmaceuticallyacceptable carriers. These may be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811 (which is incorporated herein by reference in its entirety).For example, liposome formulations may be prepared by dissolvingappropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine,stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, andcholesterol) in an inorganic solvent that is then evaporated, leavingbehind a thin film of dried lipid on the surface of the container. Anaqueous solution of the compound is then introduced into the container.The container is then swirled by hand to free lipid material from thesides of the container and to disperse lipid aggregates, thereby formingthe liposomal suspension.

Suitable vehicles or carriers for topical application can be prepared byconventional techniques, such as lotions, suspensions, ointments,creams, gels, tinctures, sprays, powders, pastes, slow-releasetransdermal patches, suppositories for application to rectal, vaginal,nasal or oral mucosa. In addition to the other materials listed abovefor systemic administration, thickening agents, emollients andstabilizers can be used to prepare topical compositions. Examples ofthickening agents include petrolatum, beeswax, xanthan gum, orpolyethylene, humectants such as sorbitol, emollients such as mineraloil, lanolin and its derivatives, or squalene.

Any of the compounds described herein for combination or alternationtherapy can be administered as any derivative that upon administrationto the recipient, is capable of providing directly or indirectly, theparent compound, or that exhibits activity itself. Nonlimiting examplesare the pharmaceutically acceptable salts (alternatively referred to as“physiologically acceptable salts”), and a compound which has beenalkylated or acylated at an appropriate position. The modifications canaffect the biological activity of the compound, in some cases increasingthe activity over the parent compound. This can easily be assessed bypreparing the derivative and testing its anti-inflammatory activityaccording to known methods.

VII. Synthesis of the Active Compounds

A number of the compounds of the general formula (I) are known, whereasmany of the compounds of the general formula (I) are novel compounds.The known compounds may be isolated or synthesized in accordance withmethods from literature or methods analogous thereto, an non-limitingexample is taught by Wade et al, Organic Chemistry Third Edition, 1995.The novel compounds may, likewise, be produced by methods known per seor methods which are analogous to such methods.

Compounds of general formula (I) are prepared by reacting an aryl orcyclic substituted ketone with an aryl or cyclic substituted aldehyde.This reaction, which is a condensation reaction, is suitably carried outunder acid or base catalyzed conditions. The reaction may be suitablycarried out in water or protic organic solvents such as lower alcohols(e.g. methanol, ethanol, or tert-butanol), or lower carboxylic acid(e.g. formic acid, glacial acetic acid, or propionic acid), or inaprotic organic solvents such as ethers (e.g. tetrahydrofuran, dioxane,or diethyl ether), liquid amides (e.g. dimethylformamide, orhexamethylphosphordiamide), dimethylsulfoxide, or hydrocarbons (e.g.toluene or benzene), or mixtures of such solvents. When carrying out thereaction under basic conditions, the base may be selected from sodium,lithium, potassium, barium, calcium, magnesium, aluminum, ammonium, orquarternary ammonium hydroxides, lower alkoxides (e.g. methoxides,ethoxides, tert-butoxides), carbonates, borates, oxides, hydrides, oramides of lower secondary amines (e.g. diisopropyl amides ormethylphenyl amides). Primary aromatic amines such as aniline, freesecondary amines such as dimethyl amine, diethyl amine, piperidine, orpyrrolidine as well as basic ion exchange resins may also be used.

Acid catalysts may be selected from hydrogen chloride, hydrogen bromide,hydrogen iodide, sulfuric acid, sulfonic acids (such asparatoluenesulfonic or methansulfonic acid), lower carboxylic acid (suchas formic, acetic, or propionic acid), lower halogenated carboxylic acid(such as trifluoroacetic acid), Lewis acids (such as BF3, POCl3, PC15,FeCl3), or acid ion exchange resins.

The reaction may be carried out at temperatures in the range of 0-100°C., preferrably at room temperature. The time of reaction may be from 30minutes to 24 hours.

In the above reactions, it may be preferred or necessary to protectvarious sensitive or reactive groups present in the starting materialsso as to prevent said groups from interfering with the reactions. Suchprotection may be carried out in a well-known manner as taught byTheodora Green et al., in “Protective Groups in Organic Chemistry” or ofthe like. The protecting group may be removed after the reaction in amanner known per se.

1,3-Bis-(substituted-phenyl)-2-propen-1-ones

The 1,3-bis-(substituted-phenyl)-2-propen-1-one compounds of formula (I)and formula (II) can be prepared by known procedures and techniques, orroutine modifications thereof. General procedures for preparingcompounds of formula (I) are set forth in Schemes 1 through 6.

Generic Syntheses

The 1,3-bis-(substituted-phenyl)-2-propen-1-one compounds of the presentinvention can be readily prepared by someone skilled in the art oforganic synthesis using commonly known methods, many of which aredescribed by D. N. Dnar in The Chemistry of Chalcones and RelatedCompounds (Wiley-Interscience, New York, 1981), that is incorporatedherein by reference. As shown in Scheme 1 through Scheme 6, typically asubstituted acetophenone is condensed with a substituted benzaldehyde inthe presence of a suitable base in a common procedure known as an aldolcondensation reaction. A variety of organic and inorganic bases can beused. Sodium hydroxide is a preferred inorganic base. The reaction canbe carried out in a variety of different solvents. Either protoic oraprotic solvents may be used. Ethanol is preferred in the presence of aninorganic base. On either or both of the phenyl rings there is a halogensubstutution, with iodo and bromo being preferred.

A heteroaryl or heterocyclic ring is then introduced to replace thehalogen substitution on either one or both of the phenyl rings through ametal-catalyzed cross-coupling carbon-carbon bond forming reaction wellknown in the art of organic chemistry. A variety of metal-catalyzedcross coupling carbon-carbon bond forming reactions can be used. Thepalladium-catalyzed Suzuki reaction is preferred, and general methodsfor this procedure are described by A. Suzuki in Recent Advances in theCross-Coupling Reactions of Organoboron Derivatives with OrganicElectrophiles, 1995-1998 (J. Organomet. Chem. (1999), 576(1-2),147-168), incorporated herein by reference. For the Suzuki reaction, avariety of solvents can be used. The preferred solvent for the Suzukicoupling is ethylene glycol dimethyl ether (DME). As shown in Schemes 1and 5, this cross-coupling reaction can be done on either phenyl ringafter the 1,3-bis-(substituted-phenyl)-2-propen-1-one skeleton has beenassembled to provide 1,3-bis-(substituted-phenyl)-2-propen-1-onescontaining one or more heteroaryl or heterocyclic ring. Alternatively,the cross-coupling reaction can be done on the individual acetophenoneor benzaldehyde intermediates prior to the aldol condensation, as shownin Schemes 2 and 4. Most of the compounds of this invention are made byeither one of these two methods.

As shown in Scheme 3, the aldol condensation reaction can also becarried out in an aquaeous solution using a surfactant. A variety ofsurfactants can be used. Cetyltrimethylammonium chloride is thepreferred surfactant. This method is particularly useful when there areone or more hydroxyl substitutions on either one or both of the phenylrings.

As shown in Scheme 6, the aldol condensation reaction can also becarried out in an aprotic solvent such as tetrahydrofuran (THF) with anorganic base. The preferred solvent is THF and the preferred base islithium diisopropylamide (LDA). In this manner an aldol reaction maytake place first and the subsequent dehydration reaction may take placeduring aqueous workup.

Some acetophenones and benzaldehydes are not commercially available.They can be readily prepared by someone skilled in the art of organicsynthesis. Since the acetophenones or benzaldehydes may also contain oneor more water solubilizing groups (amines, acohols, carboxylates,phosphates, phosphonates, sulfonates, sulfates, etc) that may interferein the reaction or that may complicate isolation of the desired product,one normally skilled in the art may choose to protect these solubilizinggroups prior to the reaction using methods commonly known in theliterature such as those described by T. W. Greene and P. G. M. Wuts inProtective Groups in Organic Synthesis (Wiley, New York, 1999) and A. J.Pearson and W. R. Roush in Handbook of Reagents for Organic Synthesis:Activating and Agents and Protecting Groups (Wiley, Chichester, UK,1999), incorporated herein by reference. Preferable protecting groupsinclude acetates to protect alcohols, esters to protect carboxylicacids, and amides or carbamates to protect amines. Compounds of thepresent invention include the resulting protected intermediates. Oneskilled in the art can selectively remove these protecting groups usingwell established and known procedures to give the desired deprotectedheteroaryl or heterocyclic 1,3-bis-(substituted-phenyl)-2-propen-1-oneproducts. Some protecting groups such as carboxylic esters may beremoved during the aldol condensation reaction. Formation of theresulting carboxylate salts, e.g. the sodium salt, may facilitateisolation of the desired heteroaryl or heterocyclic1,3-bis-(substituted-phenyl)-2-propen-1-one products from the reactionmixture. Alternatively, acidification of the reaction mixture prior toor during workup may facilitate the isolation of the desired freecarboxylic, phosphonic, phosphinic or sulfonic acid derivatives. Varioussalts of the compounds of this invention can be prepared by someoneskilled in the art of organic synthesis. Such salts, e.g. aminehydrochlorides, can be directly isolated from the reaction mixture afteracidification or formed separately after isolation of the correspondingfree amine.

The chemical reactions described above are generally disclosed in termsof their broadest applications to the preparation of the compounds ofthe present invention. Occasionally, the reactions may not be applicableas described to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In all such cases, either the reactions cansuccessfully performed by conventional modifications recognized by thoseskilled in the art, e.g., by appropriate protection and deprotection ofinterfering groups, by changing to alternative conventional solvents orreagents, by routine modification of reaction conditions and the like,or other conventional reactions will be applicable to the preparation ofthe corresponding compounds of the present invention. In all preparativemethods, all starting materials are known or readily prepared from knownstarting materials.

VIII. EXAMPLES

The following examples are understood to be illustrative only and arenot intended to limit the scope of the present invention in any way. Allintermediates and final products have been completely characterized byconventional proton NMR and standard analytical methods known to thoseskilled in the art.

Example 1:

Ex-1A: 3′,4′,5′-Trimethoxyacetophenone (1.47 g, 6.9 mmol) and3-bromo-4,5-dimethoxybenzaldehyde (1.64 g, 0.67 mmol) were suspended inethanol (50 mL). Sodium hydroxide solution (50%, 1 mL) was addeddropwise. The mixture was stirred at room temperature for 2 h. Water (20mL) was added. The precipitate was filtered out, washed with water anddried over an oil pump to give 1.91 g (65%) of the desired product,3-(3-bromo-4,5-dimethoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one,as a slightly yellow residue.

3-(3-Bromo-4,5-dimethoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one(0.105 g, 0.2 mmol) from Ex-1A was dissolved in ethylene glycol dimethylether (20 mL). Tetrakis(triphenylphosphine)palladium(0) (0.116 g, 0.1mmol) was added, and the mixture was stirred at room temperature undernitrogen for 5 min. 2-Thiopheneboronic acid (0.128 g) and sodiumcarbonate solution (2 M, 0.5 mL) were added. The mixture was stirred atreflux under nitrogen overnight. Upon cooling to room temperature it waspoured into water (100 mL) and extracted with dichloromethane (100 mL).The organic phase was dried over sodium sulfate and evaporated. Silicagel chromatography (hexane/ethyl acetate, 4:1, 2:1) gave 0.079 g (90%)of the desired3-[3,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-oneproduct as a slightly yellow residue. 1H-NMR (300 MHz, CDCl3): 7.79 (d,1H), 7.56 (m, 2H), 7.42 (d, 1H), 7.39 (d, 1H), 7.29 (s, 2H), 7.10-7.16(m, 2H), 3.89-4.00 (m, 15H). Anal. Calculated for C24H24O6S C: 65.44, H:5.49, S: 7.28; found C: 65.69, H: 5.59, S: 6.99.

Additional substituted 1-phenyl-3-[(heteroaryl)phenyl]-2-propen-1-onescan be prepared by one skilled in the art using similar methods, asshown in Example Table 1.

Example Table 1. Substituted1-Phenyl-3-[(Heteroaryl)phenyl]-2-propen-1-ones.

Ex. No. X Z Melting point (° C.) 2 2,3,4-trimethoxy 3,4-dimethoxy-5-94-97 (thien-2-yl) 3 3,4,5-trimethoxy 5-(5-acetylthien-2- 109-112yl)-3,4-dimethoxy 4 3,4,5-trimethoxy 5-(benzo[b]thien-2- 150-151yl)-3,4-dimethoxy 5 3,4,5-trimethoxy 2,4-dimethoxy-5- 75-80 (thien-2-yl)

Example 6:

Ex-6A: 5-Bromo-2,4-dimethoxybenzaldehyde (4.9 g, 20.0 mmol) wasdissolved in ethylene glycol dimethyl ether (50 mL).Tetrakis(triphenylphosphine)palladium(0) (2.32 g, 2 mmol) was added, andthe mixture was stirred at room temperature under nitrogen for 5 min.Benzo[b]thiophene-2-boronic acid (4.27 g, 24 mmol) and sodium carbonatesolution (2 M, 20 mL) were added. The mixture was stirred at refluxunder nitrogen for 24 hours. Upon cooling to room temperature, it waspoured into water and extracted with ethyl acetate. The organic phasewas dried over sodium sulfate and evaporated. Silica gel chromatography(hexane/ethyl acetate 2:1 then 1:1) gave 4.75 g (83%) of the desired5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde.

3′,4′,5′-Trimethoxyacetophenone (1.62 g, 7.7 mmol) was dissolved inethanol (50 mL). Sodium hydroxide solution (50%, 4 mL) was added and themixture was stirred at room temperature for 30 minutes.5-(Benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde (2.2 g, 7.7 mmol) fromEx-6A was added, and the mixture was stirred at room temperatureovernight. The resulting yellow precipitate was filtered out, rinsedwith water and dried over an oil pump to give 3.4 g (92%) of the desired3-[5-(benzo[b]thien-2-yl)-2,4-di-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-oneproduct as a solid, m.p. 194-196° C. 1H-NMR (300 MHz, CDCl3): 8.09 (d,1H), 7.93 (s, 1H), 7.83 (d, 1H), 7.78 (d, 1H), 7.67 (s, 1H), 7.52 (d,1H), 7.25-7.38 (m, 4H), 6.57 (s, 1H), 3.9-4.1 (m, 15H). Anal. Calculatedfor C28H26O6S: C, 68.55, H, 5.34, S, 6.53; found C: 68.48, H: 5.43, S:6.52.

Additional substituted 1-[(heteroaryl)phenyl]-3-phenyl-2-propen-1-onesand substituted 3-[(heteroaryl)phenyl]-1-phenyl-2-propen-1-ones can beprepared by one skilled in the art using similar methods, as shown inExample Tables 2a and 2b.

Example Table 2a. Substituted1-[(Heteroaryl)phenyl]-3-phenyl-2-propen-1-ones and Substituted3-[(Heteroaryl)phenyl]-1-phenyl-2-propen-1-ones.

Example Melting point No. X Z (° C.) 7 3,4,5-trimethoxy2-methoxy-5-(thien-2-yl) 47-53 8 2,4,6-trimethoxy2-methoxy-5-(thien-2-yl) 173-180 9 3,4-dimethoxy2-methoxy-5-(thien-2-yl) 124-127 10 2,6-dimethoxy2-methoxy-5-(thien-2-yl) 171-173 11 4-methoxy 2-methoxy-5-(thien-2-yl)65-85 12 3,4,5-trimethoxy 4-(thien-2-yl) 135-140 13 3,4-dimethoxy4-(thien-2-yl) 170-180 14 3,5-dimethoxy 2-methoxy-5-(thien-2-yl) 135-14015 2,5-dimethoxy 2-methoxy-5-(thien-2-yl)  96-100 16 3,4,5-trimethoxy3,4-dimethoxy-5-(3- Oil pyridyl) 17 2,5-dimethoxy-4-(thien-2-2-methoxy-5-(thien-2-yl) 54-73 yl-methoxy) 18 4-iodo-2-methoxy2-methoxy-5-(thien-2-yl) 150-155 19 3-methoxy-4-(2-2-methoxy-5-(thien-2-yl) 92-94 pyridylmethoxy) 20 3,4-dimethoxy5-(benzo[b]thien-2-yl)- 159-161 2,4-dimethoxy 21 2-methoxy-4-(3-methoxy-2-methoxy-5-(thien-2-yl)  97-107 phenyl) 22 3,4-methylenedioxy2-methoxy-5-(thien-2-yl) 140-145 23 4-(4-ethyloxy-2-methoxy-5-(thien-2-yl) 62-65 carbonylbenzyloxy)-3- methoxy 244-(4-tert-butyloxy- 2-methoxy-5-(thien-2-yl) 50-60carbonylaminobenzyloxy)- 3-methoxy 25 4-(4-aminobenzyl-oxy)-3-2-methoxy-5-(thien-2-yl) 67-80 methoxy 26 3-methoxy-4-(3-2-methoxy-5-(thien-2-yl) 220-255 pyridylmethoxy) 27 3-methoxy-4-(4-2-methoxy-5-(thien-2-yl) 165-170 pyridylmethoxy) 28 3,4,5-trimethoxy2-methoxy-5-(5- 111-115 methylthien-2-yl) 29 3,4-dimethoxy2-methoxy-5-(5- 119-124 methylthien-2-yl) 30 3,4-methylenedioxy2-methoxy-5-(5- 115-117 methylthien-2-yl) 31 3,4,5-trimethoxy2-methoxy-5-(4- 103-105 methylthien-2-yl) 32 3,4-dimethoxy2-methoxy-5-(4- 82-90 methylthien-2-yl) 33 3,4-methylenedioxy2-methoxy-5-(4- 143-146 methylthien-2-yl) 34 4-(4-carboxy-benzyloxy-2-methoxy-5-(thien-2-yl) Oil 3-methoxy 35 3,4-difluoro2-methoxy-5-(thien-2-yl) 100-105 36 3,4-dichloro-2-hydroxy2-methoxy-5-(thien-2-yl) 152-163 37 3,4,5-trimethoxy5-(benzo[b]thien-2-yl)-2- 150-151 methoxy 38 3,4-dimethoxy5-(benzo[b]thien-2-yl)-2- 155-162 methoxy 39 4-methoxy5-(benzo[b]thien-2-yl)-2- 173-176 methoxy 40 2-methoxy-5-(thien-2-yl)4-ethoxy-3-fluoro Oil 41 2,3,4-trimethoxy 2,4-dimethoxy-5-(thien-132-133 2-yl) 42 3,4-dichloro-2-hydroxy 5-(benzo[b]thien-2-yl)-2-203-210 methoxy 43 3,5-dimethoxy-4-(2- 5-(benzo[b]thien-2-yl)- 111-113morpholino-ethyloxy) 2,4-dimethoxy 44 4-carboxymethoxy-3,5-5-(benzo[b]thien-2-yl)- 145-153 dimethoxy 2,4-dimethoxy 452,3,4-trimethoxy 5-(benzo[b]thien-2-yl)- 145-147 2,4-dimethoxy 462,3,4-trimethoxy 5-(benzo[b]thien-2-yl)-2- 195-200 carboxymethoxy-4-methoxy 47

5-(benzo[b]thien-2-yl)- 2,4-dimethoxy Oil 48 4-(2,3-isopropylidene-5-(benzo[b]thien-2-yl)- 131-135 dioxy-1-propoxy)-3,5- 2,4-dimethoxydimethoxy 49 2,3,4-trimethoxy 5-(benzo[b]thien-2-yl)- 120-1243,4-dimethoxy 50 3-methoxy-4-(4- 2-methoxy-5-(thien-2-yl) 173-175pyridylmethoxy), hydrogen chloride 51 3-methoxy-4-(2-2-methoxy-5-(thien-2-yl) 168-171 pyridylmethoxy), hydrogen chloride 523,4-dichloro-2-hydroxy, 2-methoxy-5-(thien-2-yl) >260 sodium salt

EXAMPLE TABLE 2b Cyclic Substituted1-[(Heteroaryl)phenyl]-3-phenyl-2-propen-1- ones and Substituted3-[(Heteroaryl)phenyl]-1-phenyl-2-propen-1-ones. Example m.p. No.Structure (° C.) 53

216-222 54

192-205 55

164-172

Example 56:

To a suspension of 2-methoxy-5-(thien-2-yl)benzaldehyde (0.5 g, 2.3mmol), obtained in the same manner as described in Ex-6A, in 5 N KOHsolution was added cetyltrimethyl-ammonium chloride (CTACl, 25% inwater, 4 mL, 3.0 mmol) followed by the addition of4′-hydroxy-3′-methoxyacetophenone (0.38 g, 2.3 mmol). The mixture wasstirred at room temperature overnight. Then it was acidified to about pH1 with 6 M sulfuric acid, saturated with sodium chloride, and extractedwith dichloromethane. The organic phase was washed with brine, dried andevaporated. Silica gel chromatography (hexane/ethyl acetate, 3:1 then1:1) gave 0.61 g (73%) of a foam as the desired3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(4-hydroxy-3-methoxyphenyl)-2-propen-1-oneproduct, m.p. 142-144° C. 1H-NMR (300 MHz, CDCl3): 8.21 (d, 1H), 7.82(s, 1H), 7.55-7.75 (m, 4H), 6.85-7.15 (m, 4H), 6.14 (s, 1H), 4.00 (s,3H), 3.95 (s, 3H).

Example 57:

Ex-57a: 4′-iodo-2′-methoxyacetophenone (1.08 g, 3.9 mmol) in ethyleneglycol dimethyl ether (50 ml) was degassed for 15 minutes.Tetrakis(triphenylphosphine)palladium(0) (0.456 g, 0.39 mmol),thiophene-2-boronic acid (0.75 g, 5.9 mmol), and sodium carbonatesolution (2 m, 4 ml, 8 mmol) were added. The mixture was stirred atreflux under nitrogen for 24 hours. Upon cooling to room temperature, itwas poured into water and extracted with dichloromethane. The organicphase was dried over sodium sulfate and evaporated. Silica gelchromatography (hexane/ethyl acetate, 3:1) gave 0.88 g (98%) of thedesired 2′-methoxy-4′-(thien-2-yl)acetophenone.

The 2′-methoxy-4′-(thien-2-yl)acetophenone (0.30 g, 1.3 mmol) fromEx-57A and 3,4-difluorobenzaldehyde 0.19 g, 1.3 mmol) were mixed intetrahydrofuran (THF, 10 mL). Cesium carbonate (1.2 g, 3.9 mmol) wasadded, and the mixture was stirred at reflux overnight. Upon cooling toroom temperature, the mixture was filtered, the filtrate was treatedwith 0.5 M HCl, and extracted with dichloromethane. The organic phasewas dried and evaporated. Silica gel chromatography gave 0.32 g (69%) ofthe desired3-(3,4-difluorophenyl)-1-[2-methoxy-4-(thien-2-yl)phenyl]-2-propen-1-oneproduct, m.p. 73-79° C. 1H-NMR (300 MHz, CDCl3): 7.70 (d, 1H), 7.25-7.40(m, 2H), 6.98-7.15 (m, 7H), 6.49 (d, 1H), 3.89 (s, 3H).

Example 58:

The3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(4-iodo-2-methoxyphenyl)-2-propen-1-one(0.28 g, 0.59 mmol) from Example 18 was dissolved in toluene (60 mL) andethanol (10 mL), and the solution was degassed for 10 minutes. Thentetrakis(triphenyl-phosphine)palladium(0) (0.07 g, 0.05 mmol) was added,and the mixture was stirred at room temperature under nitrogen for 5min. 2-Thiopheneboronic acid (0.11 g, 0.88 mmol) and sodium carbonatesolution (2 M, 1.5 mL) were added. The mixture was stirred at refluxunder nitrogen overnight. The solvent was evaporated. Silica gelchromatography (hexane/ethyl acetate 3:1) of the resulting residue gave0.21 g (81%) of the desired3-[2-methoxy-5-(thien-2-yl)phenyl]-1-[(2-methoxy-4-(thien-2-yl)phenyl]-2-propen-1-oneproduct as a solid, m.p. 30-50° C. 1H-NMR (300 MHz, CDCl3): 7.80 (d,1H), 7.70 (d, 1H), 7.55 (d, 1H), 7.46 (m, 2H), 7.25 (d, 1H), 7.18 (d,1H), 6.95-7.08 (m, 6H), 6.80 (d, 1H), 6.76 (d, 1H), 3.96 (s, 3H), 3.85(s, 3H).

Example 59:

Ex-59A: To a solution of 4′-hydroxy-3′,5′-dimethoxyacetophenone (1 g,5.1 mmol) in N,N-dimethylformamide were added tert-butyldimethylsilylchloride (1,15 g, 7.6 mmol) and imidazole (0.69 g, 10.2 mmol). Themixture was stirred at room temperature overnight. Upon quenching with 1M sulfuric acid solution, the mixture was extracted withdichloromethane. The organic phase was washed with saturated sodiumbicarbonate and brine. It was dried and evaporated. Water (2 mL) wasadded to the residue, and the precipitate was filtered out and driedover an oil pump to give 1.28 g (81%) of3′,5′-dimethoxy-4′-(tert-butyldimethylsiloxy)acetophenone as a whitesolid, m.p. 90-92° C.

Ex-59B: To a solution of3′,5′-dimethoxy-4′-(tert-butyldimethylsiloxy)acetophenone, from Ex-59A(0.5 g, 1.6 mmol) in tetrahydrofuran (10 mL) chilled with ice/water wasadded lithium diisopropylamide (2 M, 0.8 mL, 1.6 mmol). The mixture wasstirred for 20 minutes while chilled. Then5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde, from Ex-6A,(0.48 g,1.6 mmol) in tetrahydrofuran (6 mL) was added, and the mixture wasstirred at room temperature for 2 hours. Upon quenching with water, themixture was extracted with dichloromethane. The organic phase was driedand evaporated. Crystallization from ethanol gave 0.19 g (20%) of thedesired3-[5-(benzo[b]thien-2-yl)2,4-dimethoxyphenyl]-1-(4-tert-butyldimethylsiloxy-3,5-dimethoxyphenyl)-2-propen-1-oneas a yellow solid.

To a solution of3-[5-(benzo[b]thien-2-yl)2,4-dimethoxyphenyl]-1-(4-tert-butyldimethyl-siloxy-3,5-dimethoxyphenyl)-2-propen-1-one,from Ex-59B, (0.135 g, 0.228 mmol) in tetrahydrofuran (2 mL) was addedtetrabutylammonium fluoride (0.061 g. 0.228 mmol), and the mixture wasstirred at room temperature for two hours. Upon quenching with water,the mixture was extracted with dichloromethane. The organic phase wasdried and evaporated. Silica gel chromatography (hexane/ethyl acetate,1:1) gave 0.05 g (46%) of the desired3-[5-(benzo[b]thien-2-yl)2,4-dimethoxyphenyl]-1-(4-hydroxy-3,5-dimethoxy-phenyl)-2-propen-1-oneproduct as a yellow solid, m.p. 85-105° C.

3-[5-(Benzo[b]thien-2-yl)2,4-dimethoxyphenyl]-1-(4-hydroxy-3,5-dimethoxyphenyl)-2-propen-1-onefrom Example 59 was treated with 5 N NaOH and the desired3-[5-(Benzo[b]thien-2-yl)2,4-dimethoxyphenyl]-1-(4-hydroxy-3,5-dimethoxyphenyl)-2-propen-1-onesodium salt product precipitated out following the addition ofdichloromethane, m.p. 209-215° C.

Example 61:

Ex-61A: 3′,5′-Dimethoxy-4′-hydroxyacetophenone (6.03 g, 31 mmol) andtriphenylphosphine (8.05 g, 31 mmol) were stirred in 124 mL oftetrahydrofuran (THF). The mixture was treated with ethyl glycolate (3.2g, 31 mmol) and diethylazodicarboxylate (4.83 mL, 31 mmol). The reactionmixture was stirred under reflux for about 3.5 h and then evaporated.The residue was crystallized from hexane/ethyl acetate. The motherliquor was concentrated to give a crude product which was purified byrecrystallization from EtOH twice to give 3.14 g of4′-ethoxycarbonyl-methoxy-3′,5′-dimethoxyacetophenone. Solvent removalfrom the mother liquor provided additional crude product which waspurified by silica gel chromatography (hexane/ethyl acetate, 1:1) togive additional product (4.2 g). The total amount of pure materialisolated was 7.34 g (90% yield). mp. 81-83° C.; Anal. Calcd. forCl4H18O6: C, 59.57; H, 6.43; Found: C, 59.60; H, 6.34; MS (directprobe): Calcd for Cl4H18O6: m/z=282, found: m/z=282.

4′-Ethoxycarbonylmethoxy-3′,5′-dimethoxyacetophenone from Ex-61A (3.15g; 11.2 mmol) and 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde fromEx-6A (3.33 g; 11.2 mmol) were suspended in 250 mL of absolute ethanol.The mixture was stirred and heated to give a clear solution then treateddropwise with 50% NaOH (4 mL). A yellow precipitate gradually formedafter the addition of the base. The mixture was stirred under reflux forca. 30 minutes and then cooled to room temperature and stirred for 5hours. The yellow precipitate was isolated by filtration, washed withEtOH/H2O (1:1), acetone, and hexanes. Final solvent removal underreduced pressure gave 2.4 g (39%) of the desired3-[5-(Benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(4-carboxymethoxy-3,5-di-methoxyphenyl)-2-propen-1-onesodium salt product as a yellow solid, m.p. 191-196° C. (decomp.).1H-NMR (300 MHz, DMSO-d6): 8.30 (s, 1H), 7.65-8.02 (m, 5 H), 7.31 (m,4H), 6.85 (s, 1H), 4.11 (s, 2H), 4.02 (s, 3H), 4.00 (s, 6H), 3.84 (s,6H). Anal. Calcd. for C29H25NaO8S.2.5 H2O: C, 57.90; H, 5.03; S, 5.33;Found: C, 57.53; H, 4.62; S, 5.34; MS (Neg. Ion ES): Calcd. forC29H25O8S: m/z=533, found: m/z=534.

Ex-62A: A solution of 2-hydroxy-4-methoxybenzaldehyde (3.03 g, 20 mmol)in 25 mL of dichloromethane was cooled to 0° C. and treated dropwisewith a solution of bromine (3.41 g, 21 mmol) in 10 mL ofdichloromethane. The reaction mixture was stirred at 0° C. for 1.5hours. The solvent was removed by rotary evaporation to give a residue.The residue was taken up in EtOAc and washed with 3 portions of water.The organic layer was dried over MgSO4. The drying agent was removed byfiltration, and solvent was removed by rotary evaporation to give 3.9 gof the desired 5-bromo-2-hydroxy-4-methoxybenzaldehyde as a solid, m.p.111-115° C.

Ex-62B: A stream of N2 was bubbled through a solution of5-bromo-2-hydroxy-4-methoxybenzaldehyde (1 g, 4.3 mmol) from Ex-62A in30 mL of ethylene glycol dimethyl ether for 15 min.Tetrakis-triphenylphosphine palladium (0) (0.5 g, 0.4 mmol) was addedalong with thiophene-2-boronic acid (1.2 g, 6.5 mmol) and 10 mL ofNa2CO3 (2M aqueous solution). The resulting mixture was stirred underreflux overnight. The solvent was removed by rotary evaporation and theresidue was treated with saturated NaHCO3 and extracted withdichloromethane. The organic phase was washed with brine, dried overMgSO4, and filtered to remove drying agent. Solvent was removed byrotary evaporation. Purification of the crude material by silica gelchromatography (hexanes/EtOAc, 2:1) gave 1.04 g of the desired5-benzo[b]thien-2-yl-2-hydroxy-4-methoxybenzaldehyde.

Ex-62C: A solution of5-benzo[b]thien-2-yl-2-hydroxy-4-methoxybenzaldehyde (1 g, 3.5 mmol)from Ex-62B and triphenylphosphine (1.0 g, 3.9 mmol) in 20 mL of THF wasstirred and treated with ethyl glycolate (0.4 g, 3.9 mmol) and diethylazodicarboxylate (0.7 mL, 3.9 mmol), The resulting mixture was stirredunder reflux for 2 h. The solvent was removed by rotary evaporation andthe residue was recrystallized from hexanes/EtOAc to give 0.34 g ofproduct. The mother liquor was concentrated and purified by silica gelcolumn chromatography (hexanes/EtOAc, 3:1)) to give an additional 0.07 gof product, providing a total of 0.4 g of the desired5-(benzo[b]thien-2-yl)-2-ethoxycarbonylmethoxy-4-methoxybenzaldehyde.

A solution of5-(benzo[b]thien-2-yl)-2-ethoxycarbonylmethoxy-4-methoxybenzaldehyde(0.49 g, 1.32 mmol) from Ex-62C in 100 mL of absolute EtOH was treatedwith 3′,4′,5′-trimethoxyacetophenone (0.31 g, 1.5 mmol) and 0.5 mL ofNaOH (50% aqueous solution). The yellow solution was stirred overnight.The resulting yellow precipitate was filtered and washed with 50% EtOHin water, followed by acetone. Removal of residual solvent under vacuumgave 0.66 g of thedesired,3-[5-(benzo[b]thien-2-yl)-2-carboxymethoxy-4-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-onesodium salt product, m.p. 255-257° C. 1H-NMR (300 MHz, DMSO-d6): 8.50(d, 1H), 8.09 (s, 1H), 7.75-7.90 (m, 4H), 7.51 (s, 2H), 7.28 (m, 2H),6.72 (s, 1H), 4.32 (s, 2H), 3.99 (s, 3H), 3.91 (s, 6H), 3.73 (s, 3H).

Anal. Calculated for C29H25NaO8S.2.5 H2O: C, 57.85, H, 4.97, S, 5.32;found C: 57.78, H: 4.74, S: 5.24. MS (Neg. Ion ES): Calcd. forC29H25O8S: m/z=533, found: m/z=534.

Using one or more of the preceding methods, additional substituted1-[(heteroaryl or heterocyclic)phenyl]-3-phenyl-2-propen-1-ones andsubstituted 3-[(heteroaryl orheterocyclic)phenyl]-1-phenyl-2-propen-1-ones can be prepared by oneskilled in the art using similar methods, as shown in Example Table 3through 29.

Example Table 3. Substituted 3-[5-(benzo[b]thien-2-yl)-2-carboxymethoxy-4-methoxyphenyl]-1-phenyl-2-propen-1-ones.

EXAMPLE NUMBER R2α R3α R4α R5α R6α 63 H OMe OCH2-cyclopropyl OMe H 64OMe H H H H 65 H OMe H H H 66 H H F H H 67 F H H H H 68 H F H H H 69 F FF F F 70 F H F H H 71 H F F H H 72 H F H F H 73 H OMe OCF3 OMe H 74 F HOMe H H 75 H F OMe H H 76 OH H F H H 77 OH H H F H 78 OMe H F H H 79 OMeH H F H 80 OMe H CH3 H H 81 OMe H H CH3 H 82 OMe CH3 H H H 83 OMe H H HCH3 84 H OMe F OMe H 85 H OMe Cl OMe H 86 H OMe COOH OMe H 87 H OMeOCH2COOH OMe H 88 H OMe CH2COOH OMe H 89 H OMe SCH2COOH OMe H 90 H OMeSO3H OMe H 91 H OMe SO2NH2 OMe H 92 H OMe SO2N(Me)2 OMe H 93 H OMeOCH2CH(NH2)COOH OMe H 94 H OMe NH2 OMe H 95 H OMe N(CH3)2 OMe H 96 H OMeN(H)CH2COOH OMe H 97 H OMe

OMe H 98 H OMe

OMe H 99 H OMe

OMe H 100 H OMe

OMe H 101 H OMe CH3 OMe H 102 H OMe CF3 OMe H 103 H H H H H

Example Table 4. Substituted 3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-phenyl-2-propen-1-ones

EXAMPLE NUMBER R2α R3α R4α R5α R6α 104 H OMe OCH2-cyclopropyl OMe H 105OMe H H H H 106 H OMe H H H 107 H H F H H 108 F H H H H 109 H F H H H110 F F F F F 111 F H F H H 112 H F F H H 113 H F H F H 114 H OMe OCF3OMe H 115 F H OMe H H 116 H F OMe H H 117 OH H F H H 118 OH H H F H 119OMe H F H H 120 OMe H H F H 121 OMe H CH3 H H 122 OMe H H CH3 H 123 OMeCH3 H H H 124 OMe H H H CH3 125 H OMe F OMe H 126 H OMe CI OMe H 127 HOMe COOH OMe H 128 H OMe CH2COOH OMe H 129 H OMe SCH2COOH OMe H 130 HOMe SO3H OMe H 131 H OMe SO2NH2 OMe H 132 H OMe SO2N(Me)2 OMe H 133 HOMe OCH2CH(NH2)COOH OMe H 134 H OMe NH2 OMe H 135 H OMe N(CH3)2 OMe H136 H OMe N(H)CH2COOH OMe H 137 H OMe

OMe H 138 H OMe

OMe H 139 H OMe

OMe H 140 H OMe

OMe H 141 H OMe CH3 OMe H 142 H OMe CF3 OMe H 143 H H H H H

Example Table 5. Substituted 3-[5-(thien-2-yl)-3,4-dimethoxyphenyl]-1-phenyl-2-propen-1-ones.

EXAMPLE NUMBER R2α R3α R4α R5α R6α 144 H H H H H 145 OMe H H H H 146 HOMe H H H 147 H H F H H 148 F H H H H 149 H F H H H 150 F F F F F 151 FH F H H 152 H F F H H 153 H F H F H 154 H OMe OCF3 OMe H 155 F H OMe H H156 H F OMe H H 157 OH H F H H 158 OH H H F H 159 OMe H F H H 160 OMe HH F H 161 OMe H CH3 H H 162 OMe H H CH3 H 163 OMe CH3 H H H 164 OMe H HH CH3 165 H OMe F OMe H 166 H OMe Cl OMe H 167 H OMe COOH OMe H 168 HOMe OCH2COOH OMe H 169 H OMe CH2COOH OMe H 170 H OMe SCH2COOH OMe H 171H OMe SO3H OMe H 172 H OMe SO2NH2 OMe H 173 H OMe SO2N(Me)2 OMe H 174 HOMe OCH2CH(NH2)COOH OMe H 175 H OMe NH2 OMe H 176 H OMe N(CH3)2 OMe H177 H OMe N(H)CH2COOH OMe H 178 H OMe

OMe H 179 H OMe

OMe H 180 H OMe

OMe H 181 H OMe

OMe H 182 H OMe CH3 OMe H 183 H OMe CF3 OMe H

Example Table 6. Substituted 3-[5-(heteroaryl orheterocyclic)-2,4-dimethoxyphenyl]-1-[(3,5-dimethoxy)-4-carboxymethoxyphenyl]-2-propen-1-ones.

Ex. No. R5β Ex. No. R5β Ex. No. R5β 184

190

196

185

191

197

186

192

198

187

193

199

188

194

200

189

195

201

674

206

211

202

207

212

203

208

213

204

209

214

205

210

215

Example Table 7. 3-[5-(Heteroaryl or Heterocyclic)-2-carboxymethoxy-4-methoxyphenyl]-1-[3,4,5-trimethoxy)phenyl]-2-propen-1-ones.

Ex. No. R5β Ex. No. R5β Ex. No. R5β 216

227

238

217

228

239

218

229

240

219

230

241

220

231

242

221

232

243

222

233

244

223

234

245

224

235

246

225

236

247

226

237

248

Example Table 8. 3-[5-(Heteroaryl or Heterocyclic)-2,4-dimethoxyphenyl]-1-[(3,4,5-trimethoxy)phenyl]-2-propen-1-ones.

Ex. Ex. Ex. No. R5β No. R5β No. R5β 249

252

255

250

253

256

251

254

257

258

266

274

259

267

275

260

268

276

261

269

277

262

270

278

263

271

279

264

272

280

265

273

281

Example Table 9. 3-[5-(Heteroaryl orHeterocyclic)-3,4-dimethoxyphenyl]-1-[(3,4,5-trimethoxy)phenyl]-2-propen-1-ones.

Ex. Ex. Ex. No. R5β No. R5β No. R5β 675

301

312

282

302

313

283

303

314

284

304

315

285

305

316

286

306

317

287

307

318

288

308

319

676

309

320

289

310

321

300

311

322

Example Table 10. Substituted 3-[5-(benzo[b]thien-2-yl)-4-methoxyphenyl]-1-[(3,5-dimethoxy)phenyl]-2-buten-1-ones.

Example No R4α R2β 323 OMe OMe 324 OCH2COOH OMe 325 OMe OCH2COOH

Example Table 11. 1-[4-(Heteroaryl or Heterocyclic)-phenyl]-3-[(2-carboxymethoxy-4-methoxy)phenyl]-2-propen-1-ones.

EXAMPLE NO. R2α R3α R4α R5α R6α 326 H H

H H 327 H H

H H 328 H H

H H 329 H H

H H 330 H H

H H 331 H H

H H 332 H H

H H 333 H H

H H 334 H H

H H 335 H H

H H 336 H H

H H 337 H H

H H 338 H H

H H 339 H H

H H 340 H H

H H 341 H H

H H 342 H H

H H 343 H H

H H 344 H H

H H 345 H H

H H 346 H H

H H 347 H H

H H 348 H H

H H 349 H H

H H 350 H H

H H 351 H H

H H 352 H H

H H 353 H H

H H 354 H H

H H 355 H H

H H 356 H H

H H 357 H H

H H 358 H H

H H 359 H H

H H 360 H H

H H 361 H H

H H 362 H H

H H 363 H H

H H 364 H H

H H

Example Table 12. 3-[3 or 6-(Heteroaryl)-2-carboxymethoxy-4-methoxy)phenyl]-1-[(3,4,5-trimethoxy)phenyl]-2-propen-1-ones.

Example Number R3β R5β R6β 365 H H

366 H H

367

H H 368

H H

Example Table 13. 3-[3 or 6-(Heteroaryl)-2,4-dimethoxy)phenyl]-1-[(3,4,5-trimethoxy)phenyl]-2-propen-1-ones.

Example Number R3β R5β R6β 369 H H

370 H H

371

H H 372

H H

Example Table 14. 3-[2 or 6-(Heteroaryl)-3,4-dimethoxy)phenyl]-1-[(3,4,5-trimethoxy)phenyl]-2-propen-1-ones.

Example Number R3β R5β R6β 373 H H

374 H H

375

H H 376

H H

Example Table 15. Substituted 1-[2- or 3-(Heteroaryl)-phenyl]-3-[(2-carboxymethoxy)-4-methoxyphenyl]-2-propen-1-ones.

EXAMPLE NUMBER R2α R3α R4α R5α R6α 377

H F H H 378

H F H H 379 H

F H H 380 H

F H H

Example Table 16. Substituted 1-[2- or 3-(Heteroaryl)-phenyl]-3-[(2,4-dimethoxy)phenyl]-2-propen-1-ones.

EXAMPLE NUMBER R2α R3α R4α R5α R6α 381

H F H H 382

H F H H 383 H

F H H 384 H

F H H

Example Table 17. Substituted 1-[2- or 3-(Heteroaryl)-phenyl]-3-[(3,4-dimethoxy)phenyl]-2-propen-1-ones.

EXAMPLE NUMBER R2α R3α R4α R5α R6α 385

H F H H 386

H F H H 387 H

F H H 388 H

F H H

Example Table 18. Substituted 3-[3-, 5- or6-(Heteroaryl)-2-(carboxymethoxy)-4-methoxyphenyl]-1-phenyl-2-propen-1-ones.

Example Number R3β R5β R6β 389 H

H 390 H

H 391 H H

392 H H

393

H H 394

H H

Example Table 19. Substituted 3-[3-, 5- or6-(Heteroaryl)-2,4-dimethoxyphenyl]- 1-phenyl-2-propen-1-ones.

Example Number R3β R5β R6β 395 H

H 396 H

H 397 H H

398 H H

399

H H 400

H H

Example Table 20. Substituted 3-[2-, 5- or6-(Heteroaryl)-3,4-dimethoxyphenyl]- 1-phenyl-2-propen-1-ones.

Example Number R2β R5β R6β 401 H

H 402 H

H 403 H H

404 H H

405

H H 406

H H

Example Table 21. Substituted 3-[5-(benzo[b]thien-2-yl)-4-carboxymethoxy-2-methoxyphenyl]-1-phenyl-2-propen-1-ones.

EXAMPLE NUMBER R2α R3α R4α R5α R6α 407 H OMe OCH2- OMe H cyclopropyl 408OMe H H H H 409 H OMe H H H 410 H H F H H 411 F H H H H 412 H F H H H413 F F F F F 414 F H F H H 415 H F F H H 416 H F H F H 417 H OMe OCF3OMe H 418 F H OMe H H 419 H F OMe H H 420 OH H F H H 421 OH H H F H 422OMe H F H H 423 OMe H H F H 424 OMe H CH3 H H 425 OMe H H CH3 H 426 OMeCH3 H H H 427 OMe H H H CH3 428 H OMe F OMe H 429 H OMe Cl OMe H 430 HOMe COOH OMe H 431 H OMe OCH2COOH OMe H 432 H OMe CH2COOH OMe H 433 HOMe SCH2COOH OMe H 434 H OMe SO3H OMe H 435 H OMe SO2NH2 OMe H 436 H OMeSO2N(Me)2 OMe H 437 H OMe OCH2CH(NH2) OMe H COOH 438 H OMe NH2 OMe H 439H OMe N(CH3)2 OMe H 440 H OMe N(H)CH2COOH OMe H 441 H OMe

OMe H 442 H OMe

OMe H 443 H OMe

OMe H 444 H OMe

OMe H 445 H OMe CH3 OMe H 446 H OMe CF3 OMe H 447 H OMe OMe OMe H 448OMe OMe OMe H H 449 H OMe OMe H H

Example Table 22. Substituted 3-[5-(benzo[b]thien-2-yl)-2-carboxymethoxy-4-methoxyphenyl]-1-phenyl-2-propen-1-ones.

Ex. No. Y 450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

Example Table 23. Substituted 3-[4-(heteroaryl or heterocyclic)-2,4-dimethoxyphenyl]-1-[(3,5-dimethoxy)-4-carboxymethoxyphenyl]-2-propen-1-ones.

Ex. No. R4β 490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

Example Table 24. 3-[4-(Heteroaryl or Heterocyclic)-2-carboxymethoxy-4-methoxyphenyl]-1-[(3,4,5-trimethoxy)phenyl]-2-propen-1-ones.

Ex. No. R4β 523

524

525

526

527

528

529

530

531

532

533

534

535

536

537

538

539

540

541

542

543

544

545

546

547

548

549

550

551

552

553

554

555

Example Table 25. 3-[4-(Heteroaryl or Heterocyclic)-2,4-dimethoxyphenyl]-1-[(3,4,5-trimethoxy)phenyl]-2-propen-1-ones.

Ex. No. R4β 556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

582

583

584

585

586

587

588

Example Table 26. 3-[4-(Heteroaryl or Heterocyclic)-3,5-dimethoxyphenyl]-1-[(3,4,5-trimethoxy)phenyl]-2-propen-1-ones.

Ex. No. R4β 589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

617

618

619

620

621

Example Table 27. Substituted 3-[4-(pyran-2-yl)phenyl]-1-[(3,5-dimethoxy)phenyl]-2-propen-1-ones.

Example Number R4α R2β R3β R5β 622 F OMe H OMe 623 OCH2COOH OMe OMe H624 F OCH2COOH H OMe

Example Table 28. Substituted 3-[4-(pyran-4-yl)phenyl]-1-[(3,5-dimethoxy)phenyl]-2-propen-1-ones.

Example Number R4α R2β R3β R5β 625 F OMe H OMe 626 OCH2COOH OMe OMe H627 F OCH2COOH H OMe

Example Table 29. Substituted 3-[5-(benzo[b]thien-2-yl)-2-(2-carboxy-2-propoxy)-4-methoxyphenyl]-1-phenyl-2-propen-1-ones.

Ex. No. Y 629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644

645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665

666

667

668

VIII. Biological Activity of Active Compounds

The ability of a compound described herein to inhibit the expression ofVCAM-1 in a host can be assessed using any known method, including thatdescribed in detail below.

Preparing Vascular Endothelial Cells:

Two to four confluent P150 plates were trypsinized and the cellstransferred to a 50 mL conical centrifuge tube. The cells were pelleted,resuspended and counted using the trypan blue exclusion method.

Cells were resuspended at a concentration of 36,000 cells/mL and 1 mLwas aliquoted per well.

Cells were split into 24 well tissue culture plates. The cells in eachwell should be approximately 90-95% confluent by the following day.Cells should not be older than passage 8.

Water Soluble Compounds

Compounds were initially screened at 50 μM and 10 μM. A 50 mM stocksolution for each compound was prepared in culture medium. The stocksolution was diluted to 5 mM and 1 mM. When 10 μL of the 5 mM solutionwas added to the well (1 mL medium/well), the final concentration was 50μM. Adding 10 μL of the 1 mM solution to the well provides a finalconcentration of 10 μM.

Water Insoluble Compounds

Compounds which will not go into solution in culture medium wereresuspended in DMSO at a concentration of 25 mM. The stock solution wasthen diluted to the final concentration in culture medium. The oldmedium was aspirated and 1 mL of the new medium with the compound wasadded. For example, if the final concentration was 50 μM, the 2 μL ofthe 25 mM stock was added per mL of culture medium. The 50 mM solutionwas diluted for lower concentrations.

Example 669 In Vitro MCP-1 Activity Assay

Cultured human endothelial cells were seeded in 96-well plates. On thefollowing day cells were stimulated with TNF-α (1 ng/ml) in the presenceor absence of compounds dissolved in DMSO. To establish a dose curve andIC50 for each compound, multiple concentrations in 2-fold incrementswere used. Cells were exposed to TNF-α and compounds for approximately16 hours. The next day the cells were visually examined via lightmicroscopy to score for visual signs of toxicity. Cell culture media,diluted 1:10, was analyzed by an MCP-1 immunoassay kit (R & D Systems).This assay is a sandwich immunoassay using immobilized anti-MCP-1antibody in 96-well plate to capture secreted MCP-1 in cell culturemedia. Captured MCP-1 is subsequently detected with a horse radishperoxidase-conjugated anti-MCP-1 antibody for color development. Resultsare expressed as IC50 values (the amount of compound (□M) required toachieve a 50% reduction compared to control (cells stimulated with TNF-αonly)).

Example 670 In Vitro Smooth Muscle Cell Activity Assay

Cultured human aortic smooth muscle cells were seeded in 24-well plates.When cells reached 80% confluency, they were made quiescent by changingmedia to 0.2% serum (as compared to 5% serum in normal culture media)for 48 hours. The cells were then stimulated by addition of 5% serum inthe presence or absence of compounds dissolved in DMSO. To establish adose curve and IC50 for each compound, multiple concentrations in 5-foldincrements were used. After 20 hr incubation, 3H-thymidine (0,5 μCi/perwell) was added to the cells for 4 hours of labeling. Washed cells werethen lysed in NaOH and, the amount of 3H-thymidine incorporation wasdetermined. Results are expressed as IC50 values (the amount of compound(□M) required to achieve a 50% reduction compared to control (cellsstimulated with 5% serum only)).

TABLE 3 Smooth Muscle EXAMPLE MCP-1 Activity Cell Activity NUMBER IC50(□M) IC50 (□M) 61 ND 0.45  5 ND 0.45 50 >50   0.94 51 20 1.25 41 ND 1.25 2  5 0.4  11 10 4.53  9 10 1.15  7  8 1.53 23 ND 2.33 62 ND 1.25 6 >50   0.33 ND = Not determined

Example 671 In Vitro VCAM-1 Assay

The compounds were added to the plate (each compound is done induplicate). One plate was prepared for VCAM expression and one plate wasprepared for ICAM expression.

Immediately after the compounds were added, TNF was added to each well100 units/mL TNF was usually added to each well. Since each lot of TNFvaries in the number of units, each new lot was titrated to determinethe optimum concentration. Therefore this concentration changed. If 100units/mL was being used, TNF was dilted to 10 units/μL and 10 μL addedto each well.

The plates were incubated at 37° C., 5% CO2 overnight (approximately 16hours). The next day the plates were checked under the microscope to seeif there were any visual signs of toxicity. Records were made of anycell death, debris, or morphology changes, as well as insolublecompounds (particulate or turbity).

The degree of inhibition of the compounds of formula (I) was determinedby the assays. The results are provided in Table 4.

TABLE 4

VCAM-1 IC50 X Z (□M) 4-carboxymethoxy-3,5-2,4-dimethoxy-5-(benzo[b]thien-2- 0.7 dimethoxy, sodium salt yl)2,4,6-trimethoxy 2,4-difluoro 0.7 2,3-dichloro-4-methoxy5-bromo-2-methoxy 1 2,4,6-trimethoxy 4-hydroxy-3,5-dimethoxy 13,5-dimethoxy-4-(4- 3,4,5-trimethoxy 1 methoxybenzyloxy)3,4,5-trimethoxy 5-bromo-2-methoxy 1 2,3,4-trimethoxy3-bromo-4,5-dimethoxy 1 3,4,5-trimethoxy 3,4-dimethoxy-5-phenyl 14-hydroxy-3,5-dimethoxy 2,4-dimethoxy-5-(benzo[b]thien-2- 1.2 yl)4-carboxymethoxy-3,5- 2,4-dimethoxy-5-(benzo[b]thien-2- 1.3 dimethoxyyl) 2,3,4-trimethoxy 5-(benzo[b]thien-2-yl)-3,4- 1.4 dimethoxy3,4,5-trimethoxy 2-methoxy-5-(4-methylthien-2-yl) 1.5 3,4-dimethoxy2-methoxy-5-(5-methylthien-2-yl) 1.5 3,4,5-trimethoxy2-methoxy-5-(5-methylthien-2-yl) 1.5 3,5-dimethoxy-4-(1,4-3,4,5-trimethoxy 1.5 benzodioxan-3-methoxy) 2,5-dimethoxy2-methoxy-5-(thien-2-yl) 1.5 3,4,5-trimethoxy3,4-dimethoxy-5-(thien-2-yl) 1.5 3,4-dichloro-2-hydroxy, sodium2-methoxy-5-(thien-2-yl) 1.6 salt 3,4-dimethoxy2-methoxy-5-(4-methylthien-2-yl) 2 3,4,5-trimethoxy3,4-dimethoxy-5-(3-pyridyl) 2 3,4,5-trimethoxy2,4-dimethoxy-5-(thien-2-yl) 2 3,4,5-trimethoxy 5-bromo-2,4-dimethoxy 23,5-dimethoxy 2-methoxy-5-(thien-2-yl) 2 4-iodo-2-methoxy2-methoxy-5-(thien-2-yl) 2 4-(3,4-dimethoxybenzyloxy)-3-3,4,5-trimethoxy 2 methoxy 4-(3,4-dimethoxybenzyloxy)- 3,4,5-trimethoxy2 3,5-dimethoxy 2,4,5-trimethoxy 3,4,5-trimethoxy 2 3,4,5-trimethoxy2-bromo-4,5-dimethoxy 2 3,4-dichloro-2-hydroxy 5-bromo-2-methoxy 23-methoxy-4-(3,4,5- 3,4,5-trimethoxy 2 trimethoxybenzyloxy)3-methoxy-4-(4- 2-methoxy-5-(thien-2-yl) 2 pyridylmethoxy), hydrogenchloride 3-methoxy-4-(2- 2-methoxy-5-(thien-2-yl) 2 pyridylmethoxy),hydrogen chloride 2-methoxy-4-(thien-2-yl) 3,4-difluoro 2.13,4,5-trimethoxy 5-(benzo[b]thien-2-yl)-2-methoxy 2.13,4-dichloro-2-hydroxy 2-methoxy-5-(thien-2-yl) 2.3 3,4-dimethoxy5-(benzo[b]thien-2-yl)-2-methoxy 2.4 2,3,4-trimethoxy2,4-dimethoxy-5-(thien-2-yl) 2.4 3-methoxy-4-(2-2-methoxy-5-(thien-2-yl) 2.5 pyridylmethoxy) 4-(fur-2-ylmethloxy)-3,5-3,4,5-trimethoxy 2.5 dimethoxy 4-iodo-2-methoxy 3,4,5-trimethoxy 2.52,4,6-trimethoxy 3-bromo-4,5-dimethoxy 2.5 3,4-methylenedioxy2-methoxy-5-(5-methylthien-2-yl) 2.5 4-hydroxy-3,5-dimethoxy,2,4-dimethoxy-5-(benzo[b]thien-2- 2.5 sodium salt yl) 3-methoxy-4-(3-2-methoxy-5-(thien-2-yl) 2.6 pyridylmethoxy) 4-methoxy5-(benzo[b]thien-2-yl)-2-methoxy 2.9 3,5-dimethoxy-4-(3,4-3,4,5-trimethoxy 3 methylenedioxybenzyloxy) 3,5-dimethoxy-4-(thien-2-3,4,5-trimethoxy 3 ylmethoxy) 3,4,5-trimethoxy 3-fluoro-4-methoxy 33,4-dimethoxy 3-bromo-4,5-dimethoxy 3 2,3,4-trimethoxy3,4-dimethoxy-5-(thien-2-yl) 3 3,5-dimethoxy-4-(3,4,5- 3,4,5-trimethoxy3 trimethoxybenzyloxy) 3,4,5-trimethoxy 5-(5-acetylthien-2-yl)-3,4- 3dimethoxy 4-methoxy 2-methoxy-5-(thien-2-yl) 3 2,6-dimethoxy2-methoxy-5-(thien-2-yl) 3 3,4-dimethoxy 2-methoxy-5-(thien-2-yl) 32,4,6-trimethoxy 2-methoxy-5-(thien-2-yl) 3 3,4,5-trimethoxy2-methoxy-5-(thien-2-yl) 3 5-(2,4-dimethoxyphenyl) 3,4,5-trimethoxy 32-bromo-4,5-dimethoxy 2-bromo-4,5-dimethoxy 3 3,4,5-trimethoxy 4-hydroxy3.5 3-methoxy-4-(4- 3,4,5-trimethoxy 3.7 methoxybenzyloxy)4-(4-ethoxycarbonyl- 2-methoxy-5-(thien-2-yl) 3.7 benzyloxy)-3-methoxy4-(2,3-isopropylidenedioxy-1- 5-(benzo[b]thien-2-yl)-2,4- 3.8propoxy)-3,5-dimethoxy dimethoxy 3-methoxy-4-(4-2-methoxy-5-(thien-2-yl) 4 pyridylmethoxy) 4-(3-acetylphenyl)-2-methoxy3,4,5-trimethoxy 4 3,4,5-trimethoxy 3-bromo-4,5-dimethoxy 43,4-methylenedioxy 5-bromo-2-methoxy 4 3,4-methylenedioxy2-methoxy-5-(thien-2-yl) 4 3,4-methylenedioxy2-methoxy-5-(4-methylthien-2-yl) 4 2-methoxy-5-(thien-2-yl)4-ethoxy-3-fluoro 4.3 3,4,5-trimethoxy 5-(benzo[b]thien-2-yl)-2- 4.3carboxymethoxy-4-methoxy, sodium salt 3,4,5-trimethoxy5-(benzo[b]thien-2-yl)-3,4- 5 dimethoxy 3,4,5-trimethoxy5-(benzo[b]thien-2-yl)-2,4- 5 dimethoxy 4-(4-carboxybenzyloxy)-3-2-methoxy-5-(thien-2-yl) 5 methoxy 3,5-dimethoxy-4-(2- 3,4,5-trimethoxy5 methoxyethoxy) 2,3,4-trimethoxy 5-(4-formylphenyl)-3,4-dimethoxy 52,4-dimethoxy 4-trifluoromethyl 5.3 3,4-difluoro2-methoxy-5-(thien-2-yl) 6 3,4,5-trimethoxy hydrogen 64-(3-chlorophenyl) 3,4,5-trimethoxy 6 3,4,5-trimethoxy 4-(thien-2-yl) 65-(3-chlorophenyl)-2,4- 3,4,5-trimethoxy 6 dimethoxy4-(4-aminobenzyloxy)-3- 2-methoxy-5-(thien-2-yl) 7 methoxy3-methoxy-4-(3,4- 3,4,5-trimethoxy 7 methylenedioxybenzyloxy)4-hydroxy-3-methoxy 2-methoxy-5-(thien-2-yl) 7 2,3,4-trimethoxy5-(benzo[b]thien-2-yl)-2,4- 8.1 dimethoxy 3,4,5-trimethoxy5-(benzo[b]thien-2-yl)-2- 8.3 carboxymethoxy-4-methoxy3,5-di-tert-butyl-4-methoxy hydrogen 9 3,5-dimethoxy-4-(2-5-(benzo[b]thien-2-yl)-2,4- 10 morpholinoethoxy) dimethoxy2-methoxy-4-(3- 2-methoxy-5-(thien-2-yl) 11 methoxyphenyl) 3,4-dimethoxy5-(benzo[b]thien-2-yl)-2,4- 11 dimethoxy 3,4,5-trimethoxy 4-bromo 112,5-dimethoxy-4-(thien-2-yl- 2-methoxy-5-(thien-2-yl) 12 methoxy)3,4-dimethoxy 4-(thien-2-yl) 12 2,4-dihydroxy 4-hydroxy 125-bromo-2,4-dimethoxy 3,4,5-trimethoxy 12.5 2,4,5-triethoxy3-bromo-4,5-dimethoxy 15 4-methoxy 3,4-dimethoxy 152-methoxy-4-(thien-2-yl) 2-methoxy-4-(thien-2-yl) 162,4-di-tert-butyl-3-methoxy 4-methoxy 17 hydrogen hydrogen 23 4-fluoro4-fluoro 25 hydrogen 4-nitro 30 4-methoxy hydrogen 323,4-dichloro-2-hydroxy 5-(benzo[b]thien-2-yl)-2-methoxy 50 3-chlorohydrogen 57 3,5-di-tert-butyl-4-hydroxy 4-methoxy >50 4-methyl3,5-di-tert-butyl-4-hydroxy >50 hydrogen 3,5-di-tert-butyl-4-hydroxy >503-methoxy-4-(4-tert-butyloxy- 2-methoxy-5-(thien-2-yl) >50carbonylaminobenzyloxy) hydrogen 2,4,6-triisopropyl >50 4-bromo3,4,5-trimethoxy >50 4-benzyloxy-3,5-dimethoxy 3-bromo-4,5-dimethoxy >50

5-(benzo[b]thien-2-yl)-2,4- dimethoxy >50

Alternatively, the degree of inhibition of the compounds of formula (I)was determined and tabulated in Table 5.

TABLE 5 VCAM-1 Ex. No. Structure (□M) 53

>50 54

 2 55

>50

Example 672 Mouse Peritonitis Model

FIG. 2 is a bar chart graph of the inhibition of eosinophil recruitment(percent eosinophils in the peritoneal fluid) by 50 mg/kg/dose of3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one.Balb/C mice (n=10) were sensitized to ovalbumin on days 0 and 7 with asubcutaneous injection of ovalbumin absorbed in aluminum hydroxide. Theywere then challenged with an intraperitoneal injection of ovalbumin andsacrificed 48 hrs post-challenge. Peritoneal fluid was then collectedand spun down onto slides. Slides were stained with DiffQuik and adifferential performed. The test compound was administered bysubcutaneously injection −24, −2, +2 and +6 hrs around the time ofovalbumin challenge. This is a model of allergic inflammation aseosinophils are the major leukocyte recruited into the peritoneum.

Example 673 Paw Edema Model

FIG. 3 is a bar chart graph of the inhibition of paw edema in a mousemodel of delayed type hypersensitivity by 50 mg/1 kg/dose of3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one.Balb/C mice (n=5) were sensitized intradermally on day 0 with methylatedBSA (metBSA). They were then challenged with metBSA on day 7 in theright hind paw. The animals were sacrificed 24 hours later and the leftand right hind paws weighed. The left hindpaw weight is subtracted fromthe right hind paw to give the paw weight increase. The test compoundwas administered by intraperitoneal injection −24, −2 and +6 hrs aroundthe time of metBSA challenge.

Modifications and variations of the present invention relating tocompounds that inhibit the suppression of VCAM-1 and methods of treatingdiseases mediated by the expression of VCAM-1 will be obvious to thoseskilled in the art from the foregoing detailed description of theinvention. Such modifications and variations are intended to come withthe scope of the appended claims.

1. A compound of the formula (I)

or its pharmaceutically acceptable salt, wherein: i) the wavy lineindicates that the compound can be in the form of the E or Z isomer; ii)R²² and R²³ are independently hydrogen or (C₁-C₄)alkyl; iii) R^(2α),R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β) andR^(6β) are independently hydrogen, alkyl, carbocycle, aryl, heteroaryl,heterocycle, cycloalkyl, alkoxy, aryloxy, arylalkoxy, heteroaryloxy,heteroarylalkoxy, alkylthio, alkylamino, aminoalkyl, haloalkylthio,acyl, haloalkyl, aryloxy, amido, acylamino, amino, dialkylamino,aminodialkyl, trifluoroalkoxy, alkylsulfonyl, haloalkylsulfonyl,aminocarbonyl, alkenyl, alkynyl, halogen, hydroxyl, thiol, cyano, nitro,sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid,sulfamide, sulfonamide, sulfoxide, metal sulfinate, phosphate,phosphonate, metal phosphonate, phosphinate, alditol, carbohydrate,amino acid, OC(R¹)₂CO₂H, SC(R¹)₂CO₂H, NHCHR¹CO₂H, CO—R², CO₂R¹,polyoxyalkylene, polyol alkyl, oxyalkylamino, alkylcarbonylalkyl, loweralkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl; hydroxyalkyl,aralkoxy, heteroaryl lower alkoxy, heterocyclo lower alkoxy,heteroaryloxy, heterocycleoxy, aralkyl lower thioalkyl, heteroaralkyllower thioalkyl, heterocycloalkyl lower thioalkyl, heteroaryl loweralkyl, heterocyclo lower alkyl, heteroarylthio lower alkyl, arylthiolower alkyl, heterocyclothio lower alkyl, heteroarylamino lower alkyl,heterocycloamino lower alkyl, arylsulfinyl lower alkyl, arylsulfonyllower alkyl, any of which can be optionally substituted with a moietythat does not adversely affect the biological properties of themolecule; —C(O)(CH₂)₂CO₂ ⁻M⁺, —SO₃M⁺, or -lower alkyl-O—R, wherein R isPO₂(OH)⁻M⁺, PO₃(OH)⁻M⁺ or —SO₃M⁺, wherein M⁺ is a pharmaceuticallyacceptable cation; -lower alkylcarbonyl-lower alkyl; carboxy loweralkyl; -lower alkylamino-lower alkyl; N,N-di-substituted amino loweralkyl-, wherein the substituents each independently represent loweralkyl; iv) R¹ is H, lower alkyl, an optionally substituted carbocycle,aryl, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl,alkylheteroaryl or alkylheterocycle; v) R² is an optionally substitutedalkyl, alkenyl, alkynyl, aryl, carbocycle, heteroaryl, heterocycle,alkylaryl, alkylheteroaryl, alkylheteroaryl or alkylheterocycle; vi)alternatively, R²² and R^(6α) or R²³ and R^(6α) can join together toform a bridged carbocycle, aryl, heterocycle or heteroaromatic; vii)R^(2α) and R^(3α), R^(3α) and R^(4α), R^(4α) and R^(5α), R^(5α) andR^(6α), R^(2β) and R^(3β), R^(3β) and R^(4β), R^(4β) and R^(5β) orR^(5β) and R^(6β) can independently join to form a bridged compoundselected from the group consisting of an optionally substitutedcarbocycle, an optionally substituted cycloalkenyl, an optionallysubstituted cycloalkylcarbonyl, an optionally substitutedcycloalkenylcarbonyl; an optionally substituted aryl, an optionallysubstituted heterocylic or an optionally substituted heteroaromatic, oralkylenedioxy or wherein the ring can include a carbonyl, cyclic ester,amide, amine, sulfonate, or phosphonate; viii) at least one of R^(2α),R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β) or R^(6β)is, or R^(2α) and R^(3α), R^(3α) and R^(4α), R^(4α) and R^(5α), R^(5α)and R^(6α), R^(2β) and R^(3β), R^(3β) and R^(4β), R^(4β) and R^(5β) orR^(5β) and R^(6β) come together to be, an optionally substitutedheterocycle or heteroaromatic selected from the group consisting ofpyrrolidinyl, tetrahydrofuryl, piperazinyl, piperidinyl, morpholino,thiomorpholino, tetrahydropyranyl, imidazolyl, pyrolinyl, pyrazolinyl,indolinyl, dioxolanyl, 1,4-dioxanyl, aziridinyl, furyl, furanyl,pyridyl, pyrimidinyl, benzoxazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, 1,3,4-thiadiazole, indazolyl, 1,3,5-triazinyl,isothiazolyl, imidazolyl, pyrazinyl, benzofuranyl, quinolyl,isoquinolyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl,benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl,benzothiazolyl, isothiazolyl, 1,2,4- thiadizolul, isooxazolyl, pyrrolyl,quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl,pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-oxadiazole,thiazine, pyridazine, and pteridinyl; and ix) at least one of R^(2α),R^(3α), R^(4α), R^(5α), or R^(6α), and at least one of R^(2β), R^(3β),R^(4β), R^(5β) or R^(6β) is a substituent other than hydrogen.
 2. Thecompound of claim 1 of formula (II):

or its pharmaceutically acceptable salt.
 3. The compound of claim 1,wherein R¹ is independently H or lower alkyl, R² is an optionallysubstituted alkyl; and at least one of R^(2α), R^(3α), R^(4α), R^(5α),or R^(6α), and at least one of R^(2β), R^(3β), R^(4β), R^(5β) or R^(6β)is a substituent other than hydrogen.
 4. The compound of claim 1,wherein R^(4β) or R^(5β) is optionally substituted heteroaryl orheterocycle; and at least one of R^(2α), R^(3α), R^(4α), R^(5α), orR^(6α) is a substituent other than hydrogen.
 5. The compound of claim 1,wherein R^(4α), or R^(5α) is optionally substituted heteroaryl orheterocycle; and at least one of R^(2α), R^(3α), R^(4α), R^(5α), orR^(6α) is a substituent other than hydrogen.
 6. The compound of claim 1,wherein R^(5β) ; R^(2α), R^(3α), R^(4α), R^(5α), R^(6α), or R^(2β),R^(3β), R^(4β), and R^(6β) are independently hydrogen, methoxy, ethoxy,propoxy, benzyloxy, 4-carboxybenzyloxy, 4-ethoxycarbonylbenzyloxy,4-aminobenzyloxy, fluoro, chloro, bromo, iodo, hydroxy, OCH₂CO₂H,SCH₂CO₂H, NHCH₂CO₂H, CO₂H, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy,pyrid4-ylmethoxy; fur-2-ylmethoxy, fur-3-ylmethoxy, and at least one ofR^(2α), R^(3α), R^(4α), R^(5α), or R^(6α) is a substituent other thanhydrogen.
 7. The compound of claim 1 wherein at least one of R^(2α),R^(3α), R^(4α), R^(5α), R^(6α), R^(2β), R^(3β), R^(4β), R^(5β) orR^(6β), is or R^(2α) and R^(3α), R^(3α) and R^(4α), R^(4α) and R^(5α),R^(5α) and R^(6α), R^(2β) and R^(3β), R^(3β) and R^(4β), R^(4β) andR^(5β) or R^(5β) and R^(6β) join to form a carbocycle, aryl, heterocycleor heteroaromatic in which the carbocycle, aryl, heteroaryl orheterocycle is a 5, 6 or 7 membered ring, optionally conjugated toanother carbocycle, aryl, heteroaryl or heterocycle.
 8. The compound ofclaim 1, wherein R^(3α) and R^(4α) or R^(5α) and R^(4α) join to form a5-membered methylendioxyphenyl group.
 9. The compound of claim 1,wherein a heteroaryl or heteroaryl is on the A ring.
 10. The compound ofclaim 1, wherein a heteroaryl or heteroaromatic is on the B ring. 11.The compound of claim 1, wherein the compound has a substituent thatincreases the water solubility of the compound.
 12. The compound ofclaim 11, wherein the water solubilizing moiety is selected from thegroup consisting of alkoxy, alditol, carbohydrate, amino acid,OC(R¹)₂CO₂H, SC(R¹)₂CO₂H, NHCHR¹CO₂H, CO—R² and CO₂R¹.
 13. The compoundof claim 11, wherein the solubilizing substituent is a residue ofglycolic acid.
 14. The compound of claim 11, wherein the optionallysubstituted heteroaryl or heterocyclic attached to the A or B phenylring is selected from the group consisting of pyrrolidinyl,tetrahydrofuryl, piperazinyl, piperidinyl, morpholino, thiomorpholino,tetrahydropyranyl, imidazolyl, pyrolinyl, pyrazolinyl, indolinyl,dioxolanyl, or 1,4-dioxanyl, aziridinyl, furyl, furanyl, pyridyl,pyrimidinyl, benzoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,3,4-thiadiazole, indazolyl and 1,3,5-triazinyl.
 15. The compound ofclaim 11, wherein the optionally substituted heteroaryl or heterocyclicattached to the A or B phenyl ring is selected from the group consistingof, isothiazolyl, imidazolyl, pyrazinyl, benzofuranyl, quinolyl,isoquinolyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl,benzimidazolyl, purinyl, carbazolyl, oxazolyl, benzothiazolyl,isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl,cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl, pyrazole, andimidazole.
 16. The compound of claim 11, wherein the optionallysubstituted heteroaryl or heterocyclic attached to the A or B phenylring is selected from the group consisting of 1,2,3-triazole,1,2,4-triazole, 1,2,3-oxadiazole, thiazine, pyridazine and pteridinyl.17. The compound of claim 1 the formula:

or its pharmaceutically acceptable salt thereof.
 18. The compound ofclaim 1 of the formula:

or its pharmaceutically acceptable salt.
 19. The compound of claim 1 ofthe formula:

or its pharmaceutically acceptable salt.
 20. The compound of claim 1 ofthe formula:

or its pharmaceutically acceptable salt.
 21. The compound of claim 1,wherein the compound is of the formula:

or its pharmaceutically acceptable salt.
 22. The compound of claim 1 ofthe formula:

or its pharmaceutically acceptable salt.
 23. The compound of claim 1 ofthe formula:

or its pharmaceutically acceptable salt thereof.
 24. The compound ofclaim 1 of the formula:

or its pharmaceutically acceptable salt thereof.
 25. The compound ofclaim 1 of the formula:

or its pharmaceutically acceptable salt.
 26. The compound of claim 1,the formula:

or its pharmaceutically acceptable salt.
 27. The compound of claim 1 ofthe formula:

or its pharmaceutically acceptable salt.
 28. The compound of claim 1 ofthe formula:

or its pharmaceutically acceptable salt.
 29. The compound of claim 1 ofthe formula:

wherein Y is a phenyl ring fused to another heteroaromatic orheterocycle.
 30. The compound of claim 1 of the formula:

wherein Y is a phenyl ring fused to another heteroaromatic orheterocycle.
 31. The compound of claim 1 of the formula:

or its pharmaceutically acceptable salt thereof, wherein Y is a phenylring fused to another heteroaromatic or heterocycle.
 32. The compound ofclaim 1, wherein the compound is of the formula:

or its pharmaceutically acceptable salt.
 33. The compound of claim 1,wherein the compound is of the formula:

or its pharmaceutically acceptable salt.
 34. The compound of claim 1,wherein the compound is of the formula:

or its pharmaceutically acceptable salt.
 35. The compound of claim 1 ofthe formula:

wherein R⁴¤^(β)is a heteroaryl or heterocycle.
 36. The compound of claim1 of the formula:

wherein R⁴¤^(β)is a heteroaryl or heterocycle.
 37. The compound of claim1 of the formula:

or its pharmaceutically acceptable salt, wherein R^(4β)is a heteroaraylor heterocyclic.
 38. The compound of claim 1 of the formula:

or its pharmaceutically acceptable salt, wherein R^(4β)is a heteroarylor heterocycle.
 39. The compound of claim 1 of the formula:

or its pharmaceutically acceptable salt.
 40. The compound of claim 1 ofthe formula:

or its pharmaceutically acceptable salt.
 41. A pharmaceuticalcomposition comprising an effective amount of compound any one of claims1-20, 21-31, 32-34, or 35-40 in a pharmaceutically acceptable carrier.42. The pharmaceutical composition of claim 41 further comprising asecond biologically active agent selected from the group consisting ofheparin, frusemide, ranitidine, DNAase, an immunosuppressive agent, IVgamma globulin, troleandomycin, cyclosporin (Neoral), methotrexate,FK-506, Myochrysine (gold sodium thiomalate), platelet activating factor(PAF) antagonist, thromboxane inhibitor, leukotriene-D₄-receptorantagonist, Accolate (zafirlukast), Ziflo (zileuton), leukotriene C₁ orC₂ antagonist, inhibitor of leukotriene synthesis, zileuton or aninducible nitric oxide synthase inhibitor, prophylactic agent, sodiumcromoglycate, Intal (cromolyn sodium, Nasalcrom, Opticrom, Crolom,Ophthalmic Crolom), Tilade (nedocromil, nedocromil sodium), ketotifen,β₂-adrenergic agonist, corticosteriod, antihistimine (H₁ receptorantagonist), xanthines and methylxanthines, Theo-24 (theophylline,Slo-Phylline, Uniphyllin, Slobid, Theo-Dur), Choledyl (oxitriphylline),aminophylline; anticholinergic agent (antimuscarinic agent), belladonnaalkaloids, Atrovent (ipratropium bromide), atropine, oxitropium bromide;phosphodiesterase inhibitors, zardaverine; calcium antagonists,nifedipine; potassium activators, cromakalim, P38 kinase inhibitors,tricyclic antidepressents, cJun kinase inhibitors and cylcooxygenase-2(COX-2) inhibitors.
 43. The pharmaceutical composition of claim 42,wherein the second biologically active agent is a β₂-adrenergic agonistwhich is selected from the group consisting of albuterol (salbutamol,Proventil, Ventolin), terbutaline, Maxair (pirbuterol), Serevent(salmeterol), epinephrine, metaproterenol (Alupent, Metaprel), Brethine(Bricanyl, Brethaire, terbutaline sulfate), Tomalate (bitolterol),isoprenaline, ipratropium bromide, bambuterol hydrochloride, bitolterolmeslyate, broxaterol, carbuterol hydrochloride, clenbuterolhydrochloride, clorprenaline hydrochloride, efirmnoterol fumarate,ephedra (source of alkaloids), ephedrine (ephedrine hydrochloride,ephedrine sulfate), etafedrine hydrochloride, ethylnoradrenalinehydrochloride, fenoterol hydrochloride, hexoprenaline hydrochloride,isoetharine hydrochloride, isoprenaline, mabuterol, methoxyphenaminehydrochloride, methylephedrine hydrochloride, orciprenaline sulphate,phenylephrine acid tartrate, phenylpropanolamine (phenylpropanolaminepolistirex, phenylpropanolamine sulphate), pirbuterol acetate,procaterol hydrochloride, protokylol hydrochloride, psuedoephedrine(psuedoephedrine polixtirex, psuedoephedrine tannate, psuedoephedrinehydrochloride, psuedoephedrine sulphate), reproterol hydrochloride,rimiterol hydrobromide, ritodrine hydrochloride, salmeterol xinafoate,terbutaline sulphate, tretoquinol hydrate and tulobuterol hydrochloride.44. The pharmaceutical composition of claim 42, wherein the secondbiologically active agent is a corticosteriod which is selected from thegroup consisting of glucocorticoids (GC), Aerobid (Aerobid-M,flunisolide), Azmacort (triamcinolone acetonide), Beclovet (Vanceril,beclomethasone dipropionate), Flovent (fluticasone), Pulmicort(budesonide), prednisolone, hydrocortisone, adrenaline, AlclometasoneDipropionate, Aldosterone, Amcinonide, Beclomethasone Dipropionate,Bendacort, Betamethasone (Betamethasone Acetate, Betamethasone Benzoate,Betamethasone Dipropionate, Betamethasone Sodium Phosphate,Betamethasone Valerate), Budesonide, Ciclomethasone, Ciprocinonide,Clobetasol Propionate, Clobetasone Butyrate, Clocortolone Pivalate,Cloprednol, Cortisone Acetate, Cortivazol, Deflazacort, DeoxycortoneAcetate (Deoxycortone Pivalate), Deprodone, Desonide, Desoxymethasone,Dexamethasone (Dexamethasone Acetate, Dexamethasone Isonicotinate,Dexamethasone Phosphate, Dexamethasone Sodium Metasulphobenzoate,Dexamethasone Sodium Phosphate), Dichlorisone Acetate, DiflorasoneDiacetate, Diflucortolone Valerate, Difluprednate, Domoprednate,Endrysone, Fluazacort, Fluclorolone Acetonide, Fludrocortisone Acetate,Flumethasone (Flumethasone Pivalate), Flunisolide, FluocinoloneAcetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone (FluocortoloneHexanoate, Fluocortolone Pivalate), Fluorometholone (FluorometholoneAcetate), Fluprednidene Acetate, Fluprednisolone, Flurandrenolone,Fluticasone Propionate, Formocortal, Halcinonide, HalobetasolPropionate, Halometasone, Hydrocortamate Hydrochloride, Hydrocortisone(Hydrocortisone Acetate, Hydrocortisone Butyrate, HydrocortisoneCypionate, Hydrocortisone Hemisuccinate, Hydrocortisone SodiumPhosphate, Hydrocortisone Sodium Succinate, Hydrocortisone Valerate),Medrysone, Meprednisone, Methylprednisolone (Methylprednisolone Acetate,Methylprednisolone, Hemisuccinate, Methylprednisolone Sodium Succinate),Mometasone Furoate, Paramethasone Acetate, Prednicarbate, PrednisolamateHydrochloride, Prednisolone (Prednisolone Acetate, PrednisoloneHemisuccinate, Prednisolone Hexanoate, Prednisolone Pivalate,Prednisolone Sodium Metasulphobenzoate, Prednisolone Sodium Phosphate,Prednisolone Sodium Succinate, Prednisolone Steaglate, PrednisoloneTebutate), Prednisone (Prednisone Acetate), Prednylidene, Procinonide,Rimexolone, Suprarenal Cortex, Tixocortol Pivalate, Triamcinolone(Triamcinolone Acetonide, Triamcinolone Diacetate and TriamcinoloneHexacetonide).
 45. The pharmaceutical composition of claim 42, whereinthe second biologically active agent is a antihistimine (H₁ receptorantagonist) which is selected from the group consisting of Chlortrimeton(Teldrin, chlorpheniramine), Atrohist (brompheniramine, Bromarest,Bromfed, Dimetane), Actidil (triprolidine), Dexchlor (Poladex,Polaramine, dexchlorpheniramine), Benadryl (diphen-hydramine), Tavist(clemastine), Dimetabs (dimenhydrinate, Dramamine, Marmine), PBZ(tripelennamine), pyrilamine, Marezine (cyclizine), Zyrtec (cetirizine),hydroxyzine, Antivert (meclizine, Bonine), Allegra (fexofenadine),Hismanal (astemizole), Claritin (loratadine), Seldane (terfenadine),Periactin (cyproheptadine), Nolamine (phenindamine, Nolahist), Phenameth(promethazine, Phenergan), Tacaryl (methdilazine) and Temaril(trimeprazine).
 46. A method for the treatment of an inflammatory orcardiovascular disorder in a host, comprising administering an effectiveamount of compound of claims 1-20, 21-31, 32-34, 35-40.
 47. The methodof claim 46, wherein the disorder is arthritis.
 48. The method of claim46, wherein the disorder is asthma.
 49. The method of claim 46, whereinthe disorder is dermatitis.
 50. The method of claim 46, wherein thedisorder is psoriasis.
 51. The method of claim 46, wherein the disorderis cystic fibrosis.
 52. The method of claim 46, wherein the disorder ispost transplantation late or chronic solid organ rejection.
 53. Themethod of claim 46, wherein the disorder is multiple sclerosis.
 54. Themethod of claim 46, wherein the disorder is atherosclerosis.
 55. Themethod of claim 46, wherein the disorder is post-angioplasty restenosis.56. The method of claim 46, wherein the disorder is coronary arterydisease.
 57. The method of claim 46, wherein the disorder is angina orsmall artery disease.
 58. The method of claim 46, wherein the arthritisis systemic lupus erythematosus.
 59. The method of claim 46, wherein thedisorder is Crohn's disease.
 60. The method of claim 46, wherein thedisorder is rheumatoid arthritis.
 61. The method of claim 46, whereinthe disorder is inflammatory bowel diseases.
 62. The method of claim 46,wherein the disorder is autoimmune diabetes.
 63. The method of claim 46,wherein the disorder is diabetic retinopathy.
 64. The method of claim46, wherein the disorder is rhinitis.
 65. The method of claim 46,wherein the disorder is ischemia-reperfusion injury.
 66. The method ofclaim 46, wherein the disorder is chronic obstructive pulmonary disease(COPD).
 67. The method of claim 46, wherein the disorder isglomerulonephritis.
 68. The method of claim 46, wherein the disorder isGraves disease.
 69. The method of claim 46, wherein the disorder isgastrointestinal allergies.
 70. The method of claim 46, wherein thedisorder is conjunctivitis.
 71. The method of claim 46, furthercomprising administering the compound in alternation or combination withan effective amount of a second biologically active agent.
 72. Themethod of claim 46 wherein the disorder is an inflammatory disorder. 73.The method of claim 46 wherein the disorder is a cardiovasculardisorder.